{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:27:17Z","timestamp":1783592837139,"version":"3.55.0"},"reference-count":27,"publisher":"Bioscientifica","issue":"2","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2007,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Early onset of primary hyperparathyroidism (PHPT) and multiglandular involvement suggest a familial form in which germline mutation of a PHPT-related gene(s) and a somatic event at the same locus can be often demonstrated. We investigated the involvement of multiple endocrine neoplasia type 1 (MEN1) and HRPT2 genes in a 39-year-old man with recurrent PHPT. PHPT was firstly diagnosed at the age of 21 and the patient had two recurrences separated by extended periods of normocalcemia. This unusual history prompted us to investigate other family members and study the MEN1 and HRPT2 genes. An HRPT2 germline missense mutation in exon 3 (R91P) was found in the index case, which was associated with different HRPT2 somatic alterations in each of the three examined parathyroid tumors. These findings are consistent with Knudson\u2019s \u2018two hit\u2019 concept of biallelic inactivation of classical tumor suppressor genes. Screening of 15 asymptomatic relatives was negative for the R91P germline mutation. All the three abnormal parathyroid specimens showed cystic features at histology and were negative for parafibromin immunostaining. In one specimen, diffuse parafibromin staining was evident in a rim of normal parathyroid tissue surrounding the adenomatous lesion. Our study shows that different somatic genetic events at the HRPT2 locus are responsible for the asynchronous occurrence of multiple adenomas in a patient carrying an HRPT2 germline mutation. The finding of diffuse parafibromin staining in a rim of normal parathyroid tissue, but not in the contiguous adenomatous lesion, reinforces the concept that loss of parafibromin expression is responsible for the development of parathyroid tumors in this setting.<\/jats:p>","DOI":"10.1677\/erc-06-0092","type":"journal-article","created":{"date-parts":[[2007,7,17]],"date-time":"2007-07-17T11:22:00Z","timestamp":1184671320000},"page":"493-499","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":34,"title":["Different somatic alterations of the\n                    <i>HRPT2<\/i>\n                    gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an\n                    <i>HRPT2<\/i>\n                    germline mutation"],"prefix":"10.1530","volume":"14","author":[{"given":"F","family":"Cetani","sequence":"first","affiliation":[{"name":"1Departments of Endocrinology and Metabolism,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Pardi","sequence":"additional","affiliation":[{"name":"1Departments of Endocrinology and Metabolism,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Ambrogini","sequence":"additional","affiliation":[{"name":"1Departments of Endocrinology and Metabolism,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Viacava","sequence":"additional","affiliation":[{"name":"2Oncology, Section of Pathology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Borsari","sequence":"additional","affiliation":[{"name":"1Departments of Endocrinology and Metabolism,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Lemmi","sequence":"additional","affiliation":[{"name":"1Departments of Endocrinology and Metabolism,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Cianferotti","sequence":"additional","affiliation":[{"name":"1Departments of Endocrinology and Metabolism,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Miccoli","sequence":"additional","affiliation":[{"name":"3Surgery, University of Pise, Pise, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Pinchera","sequence":"additional","affiliation":[{"name":"1Departments of Endocrinology and Metabolism,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Arnold","sequence":"additional","affiliation":[{"name":"4Center for Molecular Medicine and Division of Endocrinology & Metabolism, University of Connecticut School of Medicine, Farmington, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Marcocci","sequence":"additional","affiliation":[{"name":"1Departments of Endocrinology and Metabolism,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"2026070906005481700_ADAMI-ETAL-2002","unstructured":"Adami\n            S\n          , Marcocci C & Gatti D \n2002 Epidemiology of primary hyperparathyroidism in Europe. \nJournal of Bone and Mineral Research17 (Suppl 2) \nN18\u2013N23."},{"key":"2026070906005481700_ALDRED-ETAL-2006","doi-asserted-by":"crossref","unstructured":"Aldred\n            MJ\n          , Talacko AA, Savarirayan R, Murdolo V, Mills AE, Radden BG, Alimov A, Villablanca A & Larsson C \n2006 Dental findings in a family with hyperparathyroidism\u2013jaw tumor syndrome and a novel HRPT2 gene mutation. \nOral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics101212\u2013218.","DOI":"10.1016\/j.tripleo.2005.06.011"},{"key":"2026070906005481700_ARNOLD-ETAL-2002","unstructured":"Arnold\n            A\n          , Shattuck TM, Mallya AM, Krebs LJ, Costa J, Gallacher J, Wild Y & Saucier K \n2002 Molecular pathogenesis of primary hyperparathyroidism. \nJournal of Bone and Mineral Research17 (Suppl 2) \nN30\u2013N36."},{"key":"2026070906005481700_BRADLEY-ETAL-2005A","unstructured":"Bradley\n            KJ\n          , Hobbs MR, Buley ID, Carpten JD, Cavaco BM, Fares JE, Laidler T, Manek S, Robbins CM, Salti IS et al.2005a Uterine tumors are a phenotypic manifestation of the hyperparathyroidism\u2013jaw tumor syndrome. \nJournal of Internal Medicine25718\u201326."},{"key":"2026070906005481700_BRADLEY-ETAL-2005B","doi-asserted-by":"crossref","unstructured":"Bradley\n            KJ\n          , Cavaco BM, Bowl MR, Harding B, Young A & Thakker RV \n2005b Utilisation of a cryptic non-canonical donor splice site of the gene encoding PARAFIBROMIN is associated with familial isolated primary hyperparathyroidism. \nJournal of Medical Genetics42e51.","DOI":"10.1136\/jmg.2005.032201"},{"key":"2026070906005481700_BRADLEY-ETAL-2006","doi-asserted-by":"crossref","unstructured":"Bradley\n            KJ\n          , Cavaco BM, Bowl MR, Harding B, Cranston T, Fratter C, Besser GM, Conceicao Pereira M, Davie MW, Dudley N et al.2006 Parafibromin mutations in hereditary hyperparathyroidism syndromes and parathyroid tumours. \nClinical Endocrinology64299\u2013306.","DOI":"10.1111\/j.1365-2265.2006.02460.x"},{"key":"2026070906005481700_CARPTEN-ETAL-2002","doi-asserted-by":"crossref","unstructured":"Carpten\n            JD\n          , Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds WF, Gillanders EM, Kennedy AM, Chen JD et al.2002 HRPT2, encoding parafibromin, is mutated in hyperparathyroidism\u2013jaw tumors syndrome. \nNature Genetics32676\u2013680.","DOI":"10.1038\/ng1048"},{"key":"2026070906005481700_CETANI-ETAL-2004","doi-asserted-by":"crossref","unstructured":"Cetani\n            F\n          , Pardi E, Borsari S, Viacava P, Dipollina G, Cianferotti L, Ambrogini E, Gazzerro E, Colussi G, Berti P et al.2004 Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. \nJournal of Clinical Endocrinology and Metabolism895583\u20135591.","DOI":"10.1210\/jc.2004-0294"},{"key":"2026070906005481700_CETANI-ETAL-2007","doi-asserted-by":"crossref","unstructured":"Cetani\n            F\n          , Ambrogini E, Vacava P, Pardi E, Fanelli G, Naccarato AG, Borsari S, Lemmi M, Berti P, Miccoli P et al.2007 Should parafibromin staining replace HRPT2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma? \nEuropean Journal of Endocrinology156547\u2013554.","DOI":"10.1530\/EJE-06-0720"},{"key":"2026070906005481700_CHANDRASEKHARAPPA-ETAL-1997","doi-asserted-by":"crossref","unstructured":"Chandrasekharappa\n            SC\n          , Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang ZP, Lubenski IA, Liotta LA et al.1997 Positional cloning of the gene for multiple endocrine neoplasia-type 1. \nScience276404\u2013407.","DOI":"10.1126\/science.276.5311.404"},{"key":"2026070906005481700_DWIGHT-ETAL-2002","doi-asserted-by":"crossref","unstructured":"Dwight\n            T\n          , Nelson AE, Theodosopoulos G, Richardson AL, Learoyd DL, Philips J, Delbridge L, Zedenius J, Teh BT, Larsson C et al.2002 Independent genetic events associated with the development of multiple parathyroid tumors in patients with primary hyperparathyroidism. \nAmerican Journal of Pathology1611299\u20131306.","DOI":"10.1016\/S0002-9440(10)64406-9"},{"key":"2026070906005481700_FRIEDMAN-ETAL-1989","doi-asserted-by":"crossref","unstructured":"Friedman\n            E\n          , Sakaguchi K, Bale AE, Falchetti A, Streeten E, Zimering MB, Weinstein LS, McBride WO, Nakamura Y, Brandi ML et al.1989 Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1. \nNew England Journal of Medicine321213\u2013218.","DOI":"10.1056\/NEJM198907273210402"},{"key":"2026070906005481700_GUARNIERI-ETAL-2006","doi-asserted-by":"crossref","unstructured":"Guarnieri\n            V\n          , Scillitani A, Muscarella LA, Battista C, Bonfitto N, Bisceglia M, Minisola S, Mascia ML, D\u2019Agruma L & Cole DE \n2006 Diagnosis of parathyroid tumors in familial isolated hyperparathyroidism with HRPT2 mutation: implications for cancer surveillance. \nJournal of Clinical Endocrinology and Metabolism912827\u20132832.","DOI":"10.1210\/jc.2005-1239"},{"key":"2026070906005481700_HOWELL-ETAL-2003","doi-asserted-by":"crossref","unstructured":"Howell\n            VM\n          , Haven CJ, Kahnoski K, Khoo SK, Petillo D, Chen J, Fleuren GJ, Robinson BG, Delbridge LW, Philips J et al.2003HRPT2 mutations are associated with malignancy in sporadic parathyroid tumors. \nJournal of Medical Genetics40657\u2013663.","DOI":"10.1136\/jmg.40.9.657"},{"key":"2026070906005481700_KELLY-ETAL-2006","doi-asserted-by":"crossref","unstructured":"Kelly\n            TG\n          , Shattuck TM, Reyes-Mugica M, Stewart AF, Simonds WF, Udelsman R, Arnold A & Carpenter TO \n2006 Surveillance for early detection of aggressive parathyroid disease: carcinoma and atypical adenoma in familial isolated hyperparathyroidism associated with a germline HRPT2 mutation. \nJournal of Bone and Mineral Research211666\u20131671.","DOI":"10.1359\/jbmr.060702"},{"key":"2026070906005481700_LARSSON-ETAL-1988","doi-asserted-by":"crossref","unstructured":"Larsson\n            C\n          , Skogseid B, Oberg K, Nakamura Y & Nordenskold M \n1988 Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. \nNature33285\u201387.","DOI":"10.1038\/332085a0"},{"key":"2026070906005481700_MARX-2000","unstructured":"Marx\n            SJ\n          \n          2000 Hyperparathyroidism and hypoparathyroidism disorders. \nNew England Journal of Medicine3431863\u20131875."},{"key":"2026070906005481700_MARX-ETAL-2002","unstructured":"Marx\n            SJ\n          , Simonds WF, Agarwal SK, Burns AL, Weinstein LS, Cochran C, Skarulis MC, Spiegel AM, Libutti SK, Alexander HR Jr et al.2002 Hyperparathyroidism in hereditary syndromes: special expressions and special managements. \nJournal of Bone and Mineral Research17 (Suppl 2) \nN37\u2013N43."},{"key":"2026070906005481700_MIZUSAWA-ETAL-2006","doi-asserted-by":"crossref","unstructured":"Mizusawa\n            N\n          , Uchino S, Iwata T, Tsuyuguchi M, Suzuki Y, Mizukoshi T, Yamashita Y, Sakurai A, Suzuki S, Beniko M et al.2006 Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism\u2013jaw tumour syndrome. \nClinical Endocrinology659\u201316.","DOI":"10.1111\/j.1365-2265.2006.02534.x"},{"key":"2026070906005481700_MOON-ETAL-2005","doi-asserted-by":"crossref","unstructured":"Moon\n            SD\n          , Park JH, Kim EM, Kim JH, Han JH, Yoo SJ, Yoon KH, Kang MI, Lee KW, Son HY et al.2005 A novel IVS2-1G&gt;A mutation causes aberrant splicing of the HRPT2 gene in a family with hyperparathyroidism\u2013jaw tumor syndrome. \nJournal of Clinical Endocrinology and Metabolism90878\u2013883.","DOI":"10.1210\/jc.2004-0991"},{"key":"2026070906005481700_PANNETT-AND-THAKKER-2001","doi-asserted-by":"crossref","unstructured":"Pannett\n            AA\n           & Thakker RV \n2001 Somatic mutations in MEN type 1 tumors, consistent with the Knudson \u2018two-hit\u2019 hypothesis. \nJournal of Clinical Endocrinology and Metabolism864371\u20134374.","DOI":"10.1210\/jcem.86.9.7844"},{"key":"2026070906005481700_SHATTUCK-ETAL-2003","doi-asserted-by":"crossref","unstructured":"Shattuck\n            TM\n          , Valimaki S, Obara T, Gaz RD, Clark OH, Shoback D, Wierman ME, Tojo K, Robbins CM, Carpten JD et al.2003 Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid Carcinoma. \nNew England Journal of Medicine3491722\u20131729.","DOI":"10.1056\/NEJMoa031237"},{"key":"2026070906005481700_SIMONDS-ETAL-2004","doi-asserted-by":"crossref","unstructured":"Simonds\n            WF\n          , Robbinc CM, Agarwal SK, Hendy GN, Carpten JD & Marx SJ \n2004 Familial isolated hyperparathyroidism is rarely caused by germline mutations in HRPT2, the gene for the hyperparathyroidism\u2013jaw tumor syndrome. \nJournal of Clinical Endocrinology and Metabolism8996\u2013102.","DOI":"10.1210\/jc.2003-030675"},{"key":"2026070906005481700_TAN-ETAL-2004","doi-asserted-by":"crossref","unstructured":"Tan\n            MH\n          , Morrison C, Wang P, Yang X, Haven CJ, Zhang C, Zhao P, Tretiakova MS, Korpi-Hyovalti E, Burgess JR et al.2004 Loss of parafibromin immunoreactivity is a distinguishing feature of parathyroid carcinoma. \nClinical Cancer Research106629\u20136637.","DOI":"10.1158\/1078-0432.CCR-04-0493"},{"key":"2026070906005481700_THAKKER-ETAL-1989","doi-asserted-by":"crossref","unstructured":"Thakker\n            RV\n          , Bouloux P, Wooding C, Chotai K, Broad PM, Spurr NK, Besser GM & O\u2019Riordan JL \n1989 Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11. \nNew England Journal of Medicine321218\u2013224.","DOI":"10.1056\/NEJM198907273210403"},{"key":"2026070906005481700_VILLABLANCA-ETAL-2004","doi-asserted-by":"crossref","unstructured":"Villablanca\n            A\n          , Calender A, Forsberg L, Hoog A, Cheng JD, Petillo D, Bauters C, Kahnoski K, Ebeling T, Salmela P et al.2004 Germline and de novo mutations in the HRPT2 tumor suppressor gene in familial isolated hyperparathyroidism (FIHP). \nJournal of Medical Genetics41e32.","DOI":"10.1136\/jmg.2003.012369"},{"key":"2026070906005481700_YAMASHITA-ETAL-2007","doi-asserted-by":"crossref","unstructured":"Yamashita\n            Y\n          , Akiyama T, Mizusawa N, Yoshimoto K & Goto M \n2007 A case of hyperparathyroidism\u2013jaw tumor syndrome found in the treatment of an ossifying fibroma in the maxillary bone. \nInternational Journal of Oral and Maxillofacial Surgery36365\u2013369.","DOI":"10.1016\/j.ijom.2006.08.007"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/14\/2\/0140493.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/14\/2\/493\/150462\/0140493.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/14\/2\/493\/150462\/0140493.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:01:30Z","timestamp":1783591290000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article\/14\/2\/493\/26766\/Different-somatic-alterations-of-the-HRPT2-gene-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,6,1]]},"references-count":27,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2007,6,1]]}},"URL":"https:\/\/doi.org\/10.1677\/erc-06-0092","relation":{},"ISSN":["1479-6821","1351-0088"],"issn-type":[{"value":"1479-6821","type":"electronic"},{"value":"1351-0088","type":"print"}],"subject":[],"published":{"date-parts":[[2007,6,1]]}}}