Abstract
Hyperparathyroidism–jaw tumour syndrome (HPT-JT) is a rare variant of familial hyperparathyroidism, characterized by primary hyperparathyroidism (PHPT) due to one or multiple parathyroid adenomas, and benign tumours of the mandible and maxilla. It has an autosomal dominant pattern of inheritance, and is associated with mutations that deactivate the cell division cycle protein 73 homolog (CDC73) gene, also known as hyperparathyroidism 2 (HRPT2), located on the long arm of chromosome 1, that encodes for the tumour suppressor protein parafibromin. In the majority of cases, PHPT is the presenting symptom, but up to 30 % of HPT-JT cases initially present with an ossifying fibroma of the maxillofacial bones. HPT-JT may result in severe hypercalcemia-related complications and an elevated risk of parathyroid carcinoma. For this reason, early identification of the disease is important. We present the case of a 23-year-old woman who was found to have jaw tumours and was later diagnosed with PHPT. Genetic analysis revealed a novel mutation in exon 1 of CDC73. This report contributes to the understanding of the genetics of this rare syndrome. It also highlights the fact that HPT-JT should be considered and CDC73 mutation analysis should be performed in cases of early-onset PHPT associated with ossifying fibromas of the jaw.
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Jackson CE, Norum RA, Boyd SP, Talpos GB, Wilson SD, Taqqart RT et al. Hereditary hyperparathyroidism and multiple ossifying jaw fibromas: a clinically and genetically distinct syndrome. Surgery 1990;108:1006-1012.
Iacobone M, Masi G, Barzon L, Porzionato A, Macchi V, Ciarleglio FA et al. Hyperparathyroidism-jaw tumour syndrome: a report of three large kindred. Langenbecks Arch Surg. 2009; 394: 817-25.
Aldred MJ, Talacko AA, Savarirayan R, Murdolo V, Mills AE, Radden BG et al. Dental findings in a family with hyperparathyroidism-jaw tumour syndrome and a novel HRPT2 gene mutation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006; 101: 212-8
Braley KJ, Hobbs MR, Buley ID, Carpten JD, Cavaco BM, Fares JE et al. Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome. J Intern Med. 2005; 257: 18-26.
McCarthy EF. Fibro-osseous lesions of the maxillofacial bones. Head Neck Pathol. 2013;7:5–10.
Yamashita Y, Akiyama T, Mizusawa N, Yoshimoto K, Goto M. A case of hyperparathyroidism-jaw tumour syndrome found in the treatment of an ossifying fibroma in the maxillary bone. Int J Oral Maxillofac Surg 2007;36(4):365-9.
Mathews JW, Winchester R, Alsaygh N, Bartlett AM, Luttrell LM. Hyperparathyroidism-jaw tumour syndrome-an overlooked cause of severe hypercalcemia. Am J Med Sci. 2015 [Epub ahead of print]
Bradley KJ, Thakker RV. The Hyperparathyroidism-jaw tumour (HPT-JT) syndrome. Clin Cases Miner Bone Res 2006;3:167–174.
Szabó J, Heath B, Hill VM, Jackson CE, Zarbo RJ, Mallette LE et al. Hereditary hyperparathyroidism-jaw tumour syndrome: the endocrine tumour gene HRPT2 maps to chromosome 1q21-q31. Am J Hum Genet 1995; 56: 944-50.
Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J et al. HRPT2, encoding parafibromin, is mutated in hyperparathryroidism-jaw tumour syndrome. Nat Genet 2002; 32: 676-80.
Bradley KJ, Bowl MR, Williams SE, Ahmad BN, Partridge CJ, Patmanidi AL et al. Parafibromin is a nuclear protein with a functional monopartite nuclear localization signal. Oncogene 2007; 26:1213–1221.
Hahn MA, Marsh DJ. Identification of a functional bipartite nuclear localization signal in the tumour suppressor parafibromin. Oncogene 2005; 24:6241–6248.
Newey PJ, Bowl MR, Cranston T, Thakker RV. Cell division cycle protein 73 homolog (CDC73) mutations in the hyperparathyroidism-jaw tumour syndrome (HPT-JT) and parathyroid tumours. Hum Mutat 2010; 31: 295-307.
Kennett S, Pollick H. Jaw lesions in familial hyperparathyroidism. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1971; 31:502-10.
Rosen IB, Palmer JA. Fibro-osseous tumours of the facial skeleton in association with primary hyperparathyroidism: an endocrine syndrome or coincidence? Am J Surg 1981;142:494-8.
Warnakulasuriya S, Markwell BD, Williams DM. Familial hyperparathyroidism associated with cementifying fibromas of the jaws in two siblings. Oral Surg Oral Med Oral Path Oral Radiol Endod 1985;59:269-74.
Cavaco BM, Barros L, Pannet AA, Ruas L, Carvalheiro M, Ruas MM et al. Hyperparathyroidism-jaw tumour syndrome in a Portuguese kindred. QJM. 2001; 94: 213-22.
Cavaco BM, Guerra L, Bradley KJ, Carvalho D, Harding B, Oliveira A, Santos MA, Sobrinho LG, Thakker RV, Leite V. Hyperparathyroidism-jaw tumour syndrome in Roma families from Portugal is due to a founder mutation of the HRPT2 gene. J Clin Endocrinol Metab 2004; 89:1747–1752.
Haven CJ, Wong FK, van Dam EW, van der Juijt R, van Asperen C, Jansen J et al. A genotypic and histopathological study of a large Dutch kindred with hyperparathyroidism-jaw tumour syndrome. J Clin Endocrinol Metab 2000; 85:1449–1454.
Rekik N, Ben Naceur B, Mnif M, Mnif F, Mnif H, Boudawara T. Hyperparathyroidism-jaw tumour syndrome: a case report. Ann Endocrinol (Paris). 2010; 71(2):121-6.
Carlson AL, Smith CL. Primary hyperparathyroidism and jaw tumour syndrome: a novel mutation of the HRPT2 gene. Endocr Pract 2008;14(6):743-7.
Abdulla AG, O’Leary EM, Isorena JP, Diaz MF, Yeh MW. Recurrent hyperparathyroidism and a novel nonsense mutation in a patient with hyperparathyroidism-jaw tumour syndrome. Endocr Pract 2013; 19: 134-7.
Sharretts JM, Simonds WF. Clinical and molecular genetics of parathyroid neoplasms. Best Pract Res Clin Endocrinol Metab. 2010; 24: 491-502.
Marx SJ, Simonds WF, Agarwal SK, Burns AL, Weinstein LS, Cochran C et al. Hyperparathyroidism in hereditary syndromes: special expressions and special managements. J Bone Miner Res 2002; 17: 37-43.
B Veiguela, ML Isidro, S Jorge y B Ruano. Una causa rara de hipercalcemia: carcinoma sincrónico de dos paratiroides en el contexto del síndrome de hiperparatiroidismo familiar-tumour mandibular. Endocrinol Nutr. 2010; 57: 391-399.
Vito G, Alfredo S, Lucia Anna M, Claudia B, Nazzareno B, Michele B et al. Diagnosis of Parathyroid Tumours in Familial Isolated Hyperparathyroidism with HRPT2 Mutation: Implications for Cancer Surveillance. J Clin Endocrinol Metab. 2006; 91: 2827-2832.
Sarquis MS, Silveira LG, Pimenta FJ, Dias EP, Teh BT, Friedman E, et al. Familial hyperparathyroidism: surgical outcome after 30 years of follow-up in three families with germline HRPT2 mutations. Surgery. 2008; 143(5):630–40
Barry MK, van Heerden JA, Grant CS, Thompson GB, Khosla S. Is familial hyperparathyroidism a unique disease? Surgery. 1997; 122(6):1028–33
Huang SM, Duh QY, Shaver J, Siperstein AE, Kraimps JL, Clark OH. Familial hyperparathyroidism without multiple endocrine neoplasia. World J Surg. 1997; 21(1):22–8.
Mehta A, Patel D, Rosenberg A, Boufraqech M, Ellis RJ, Nilubol N et al. Hyperparathyroidism-jaw tumour syndrome: Results of operative management. Surgery. 2014; 156(6):1315-24.
T. Carling, R. Udelsman. Parahyroid surgery in familial parathyroid disorders. J Intern Med. 2005; 257: 27-37.
Sharretts JM, Kebebew E, Simonds WF. Parahyroid cancer. Semin Oncol. 2010; 37: 580-90.
Chen JD, Morrison C, Zhang C, Kahnoski K, Carpten JD, Teh BT. Hyperparathyroidism-jaw tumour syndrome. J Intern Med. 2003; 253: 634-42.
Tan MH1, Teh BT. Renal neoplasia in the hyperparathyroidism-jaw tumour syndrome. Curr Mol Med 2004;4(8):895-7.
Teh BT, Farnebo F, Kristoffersson U, Sundelin B, Cardinal J, Axelson R et al. Autosomal dominant primary hyperparathyroidism and jaw tumour syndrome associated with renal hamartomas and cystic kidney disease: linkage to 1q21-q32 and loss of the wild type allele in renal hamartomas. J Clin Endocrinol Metab. 1996; 81: 4204-11.
Kutcher MR, Rigby MH, Bullock M, Trites J, Taylor SM, Hart RD. Hyperparathyroidism-jaw tumour syndrome. Head Neck. 2013; 35: 175-7.
Gill AJ, Clarkson A, Gimm O, Keil J, Dralle H, Howell VM et al. Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyroidism-jaw tumour (HPT-JT) syndrome-related adenomas from sporadic parathyroid adenomas and hyperplasias. Am J Surg Pathol. 30(9):1140-9.
Frank-Raue K, Haag C, Schulze E et al. CDC73-related hereditary hyperparathyroidism: five new mutations and the clinical spectrum. Eur J Endocrinol. 2011; 165: 477-483.
Khadilkar KS, Budyal SR, Kasliwal R, Lila AR, Bandgar T, Shah NS. HRPT2- (CDC73) related hereditary hyperparathyroidism: a case series from western india. Endocr Pract. 2015; 21:1010-6.
Shibata Y, Yamazaki M, Takei M, Uchino S, Sakurai A, Komatsu M. Early-onset, severe, and recurrent primary hyperparathyroidism associated with a novel CDC73 mutation. Endocr J. 2015; 62:627-32.
Silveira LG, Dias EP, Marinho BC, Gomez RS, De Marco L, Sarquis MS. HRPT2-related familial isolated hyperparathyroidism: could molecular studies direct the surgical approach? Arq Bras Endocrinol Metabol. 2008; 52:1211-20.
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Bellido, V., Larrañaga, I., Guimón, M. et al. A Novel Mutation in a Patient with Hyperparathyroidism–Jaw Tumour Syndrome. Endocr Pathol 27, 142–146 (2016). https://doi.org/10.1007/s12022-016-9427-6
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DOI: https://doi.org/10.1007/s12022-016-9427-6