Nothing Special   »   [go: up one dir, main page]
Skip to main content

Advertisement

Springer Nature Link
Log in

A large extended family with hyperparathyroidism-jaw tumor syndrome due to deletion of the third exon of CDC73: clinical and molecular features

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

We described the phenotype of a large 4-generation family with Hyperparathyrodism-Jaw Tumor syndrome (HPT-JT) associated with a rare deletion of exon 3 of the CDC73 gene.

Methods

We collected medical, genetic data on 24 family members descended from a common ancestor carrying a heterozygous deletion of exon 3.

Results

Thirteen carried the deletion, the penetrance was estimated at 50% at 40 years. Seven patients (39 ± 14.5 years) presented with HPT which could start at 13. Median plasmatic calcium and PTH levels were 3.13 ± 0.7 mmol/L and 115 ± 406 pg/ml, respectively. Kidney disease related to hypercalcemia were present in 57.1% of patients. All seven patients underwent surgery to remove a single parathyroid adenoma. One recurrence occurred 7 years post-surgery. No parathyroid carcinoma has been found to date. We found two atypical parathyroid adenomas. We described an additional somatic variant in exon 1 of gene CDC73 in two tumors. Jaw tumors were not necessarily associated with hyperparathyroidism, as shown in one case. Two kidney cysts were also reported. Variable phenotype expressivity was emphasized by clinical presentations in 2 monozygotic twins: acute hypercalcemia, kidney failure and ossifying fibroma in one twin, versus normocalcemic parathyroid adenoma in the other one.

Conclusion

We report a family carrier of a deletion of exon 3 of the CDC73 gene. This is characterized by a high level of hypercalcemia, deleterious kidney effects and atypical parathyroid adenomas without carcinomas. Onset and intensity of HPT remain unpredictable. The additional somatic mutation found in the parathyroid tumor could lead to these phenotypical variations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. W.D. Fraser, Hyperparathyroidism. Lancet Lond. Engl. 374, 145–58 (2009)

    Article  CAS  Google Scholar 

  2. M.W. Yeh, P.H.G. Ituarte, H.C. Zhou, S. Nishimoto, I.-L.A. Liu, A. Harari, P.I. Haigh, A.L. Adams, Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. J. Clin. Endocrinol. Metab. 98, 1122–9 (2013)

    Article  CAS  Google Scholar 

  3. J.M. Sharretts, W.F. Simonds, Clinical and molecular genetics of parathyroid neoplasms. Best. Pract. Res. Clin. Endocrinol. Metab. 24, 491–502 (2010)

    Article  CAS  Google Scholar 

  4. D.J. Marsh, M.A. Hahn, V.M. Howell, A.J. Gill, Molecular diagnosis of primary hyperparathyroidism in familial cancer syndromes. Expert Opin. Med. Diagn. 1, 377–92 (2007)

    Article  CAS  Google Scholar 

  5. S.M. Hyde, T.A. Rich, S.G. Waguespack, N.D. Perrier, and M.I. Hu, In GeneReviews®, ed. by M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. Bean, K. Stephens, and A. Amemiya (University of Washington, Seattle, Seattle (WA), 1993).

  6. C.E. Jackson, Hereditary hyperparathyroidism associated with recurrent pancreatitis. Ann. Intern. Med. 49, 829–36 (1958)

    Article  CAS  Google Scholar 

  7. C.E. Jackson, R.A. Norum, S.B. Boyd, G.B. Talpos, S.D. Wilson, R.T. Taggart, L.E. Mallette, Hereditary hyperparathyroidism and multiple ossifying jaw fibromas: a clinically and genetically distinct syndrome. Surgery 108, 1006–12 (1990)

    CAS  PubMed  Google Scholar 

  8. L.E. Mallette, S. Malini, M.P. Rappaport, J.L. Kirkland, Familial cystic parathyroid adenomatosis. Ann. Intern. Med. 107, 54–60 (1987)

    Article  CAS  Google Scholar 

  9. J. Szabó, B. Heath, V.M. Hill, C.E. Jackson, R.J. Zarbo, L.E. Mallette, S.L. Chew, G.M. Besser, R.V. Thakker, V. Huff, Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21-q31. Am. J. Hum. Genet. 56, 944–50 (1995)

    PubMed  PubMed Central  Google Scholar 

  10. J.D. Carpten, C.M. Robbins, A. Villablanca, L. Forsberg, S. Presciuttini, J. Bailey-Wilson, W.F. Simonds, E.M. Gillanders, A.M. Kennedy, J.D. Chen, S.K. Agarwal, R. Sood, M.P. Jones, T.Y. Moses, C. Haven, D. Petillo, P.D. Leotlela, B. Harding, D. Cameron, A.A. Pannett, A. Höög, H. Heath, L.A. James-Newton, B. Robinson, R.J. Zarbo, B.M. Cavaco, W. Wassif, N.D. Perrier, I.B. Rosen, U. Kristoffersson, P.D. Turnpenny, L.-O. Farnebo, G.M. Besser, C.E. Jackson, H. Morreau, J.M. Trent, R.V. Thakker, S.J. Marx, B.T. Teh, C. Larsson, M.R. Hobbs, HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome. Nat. Genet. 32, 676–80 (2002)

    Article  CAS  Google Scholar 

  11. O. Rozenblatt-Rosen, C.M. Hughes, S.J. Nannepaga, K.S. Shanmugam, T.D. Copeland, T. Guszczynski, J.H. Resau, M. Meyerson, The parafibromin tumor suppressor protein is part of a human Paf1 complex. Mol. Cell. Biol. 25, 612–20 (2005)

    Article  CAS  Google Scholar 

  12. A.G. Knudson, Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. U. S. A 68, 820–823 (1971)

    Article  Google Scholar 

  13. F. Cetani, E. Pardi, E. Ambrogini, P. Viacava, S. Borsari, M. Lemmi, L. Cianferotti, P. Miccoli, A. Pinchera, A. Arnold, C. Marcocci, Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation. Endocr. Relat. Cancer 14, 493–9 (2007)

    Article  CAS  Google Scholar 

  14. F. Torresan, M. Iacobone, Clinical Features, Treatment, and Surveillance of Hyperparathyroidism-Jaw Tumor Syndrome: an Up-to-Date and Review of the Literature. Int J. Endocrinol. 2019, 1761030 (2019)

    Article  Google Scholar 

  15. Y. Li, J. Zhang, P.R. Adikaram, J. Welch, B. Guan, L.S. Weinstein, H. Chen, W.F. Simonds, Genotype of CDC73 germline mutation determines risk of parathyroid cancer. Endocr. Relat. Cancer 27, 483–94 (2020)

    Article  CAS  Google Scholar 

  16. C.J. Haven, F.K. Wong, E.W. van Dam, R. van der Juijt, C. van Asperen, J. Jansen, C. Rosenberg, M. de Wit, J. Roijers, J. Hoppener, C.J. Lips, C. Larsson, B.T. Teh, H. Morreau, A genotypic and histopathological study of a large Dutch kindred with hyperparathyroidism-jaw tumor syndrome. J. Clin. Endocrinol. Metab. 85, 1449–54 (2000)

    CAS  PubMed  Google Scholar 

  17. K. Van der Tuin, C.M.J. Tops, M.A. Adank, J.-M. Cobben, N.A.T. Hamdy, M.C. Jongmans, F.H. Menko, B.P.M. van Nesselrooij, R.T. Netea-Maier, J.C. Oosterwijk, G.D. Valk, B.H.R. Wolffenbuttel, F.J. Hes, H. Morreau, CDC73-Related Disorders: clinical Manifestations and Case Detection in Primary Hyperparathyroidism. J. Clin. Endocrinol. Metab. 102, 4534–40 (2017)

    Article  Google Scholar 

  18. L. Bricaire, M.-F. Odou, C. Cardot-Bauters, B. Delemer, M.-O. North, S. Salenave, D. Vezzosi, J.-M. Kuhn, A. Murat, P. Caron, J.-L. Sadoul, C. Silve, P. Chanson, A. Barlier, E. Clauser, N. Porchet, L. Groussin, Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 98, E403–E408 (2013)

    Article  CAS  Google Scholar 

  19. S. Richards, N. Aziz, S. Bale, D. Bick, S. Das, J. Gastier-Foster, W.W. Grody, M. Hegde, E. Lyon, E. Spector, K. Voelkerding, H.L. Rehm; ACMG Laboratory Quality Assurance Committee. Genet. Med. J. Am. Coll. Med. Genet. 17, 405 (2015)

    Google Scholar 

  20. M. Fujikawa, K. Okamura, K. Sato, T. Mizokami, K. Tamaki, T. Yanagida, M. Fujishima, Familial isolated hyperparathyroidism due to multiple adenomas associated with ossifying jaw fibroma and multiple uterine adenomyomatous polyps. Eur. J. Endocrinol. 138, 557–61 (1998)

    Article  CAS  Google Scholar 

  21. K.J. Bradley, M.R. Hobbs, I.D. Buley, J.D. Carpten, B.M. Cavaco, J.E. Fares, P. Laidler, S. Manek, C.M. Robbins, I.S. Salti, N.W. Thompson, C.E. Jackson, R.V. Thakker, Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome. J. Intern. Med. 257, 18–26 (2005)

    Article  CAS  Google Scholar 

  22. M.H. Tan, B.T. Teh, Renal neoplasia in the hyperparathyroidism-jaw tumor syndrome. Curr. Mol. Med. 4, 895–7 (2004)

    Article  CAS  Google Scholar 

  23. D. Betea, I. Potorac, A. Beckers, Parathyroid carcinoma: challenges in diagnosis and treatment. Ann. Endocrinol. 76, 169–77 (2015)

    Article  Google Scholar 

  24. A.R. Pichardo-Lowden, A. Manni, B.D. Saunders, M.J. Baker, Familial hyperparathyroidism due to a germline mutation of the CDC73 gene: implications for management and age-appropriate testing of relatives at risk. Endocr. Pract. J. Am. Coll. Endocrinol. Am. Assoc. Clin. Endocrinol. 17, 602–9 (2011)

    Google Scholar 

  25. T.G. Kelly, T.M. Shattuck, M. Reyes-Mugica, A.F. Stewart, W.F. Simonds, R. Udelsman, A. Arnold, T.O. Carpenter, Surveillance for early detection of aggressive parathyroid disease: carcinoma and atypical adenoma in familial isolated hyperparathyroidism associated with a germline HRPT2 mutation. J. Bone Miner. Res. J. Am. Soc. Bone Miner. Res. 21, 1666–71 (2006)

    Article  CAS  Google Scholar 

  26. A. Galani, R. Morandi, M. Dimko, S. Molfino, C. Baronchelli, S. Lai, F. Gheza, C. Cappelli, C. Casella, Atypical parathyroid adenoma: clinical and anatomical pathologic features. World J. Surg. Oncol. 19, 19 (2021)

    Article  Google Scholar 

  27. L.M. Panicker, J.-H. Zhang, P.K. Dagur, M.J. Gastinger, W.F. Simonds, Defective nucleolar localization and dominant interfering properties of a parafibromin L95P missense mutant causing the hyperparathyroidism–jaw tumor syndrome. Endocr. Relat. Cancer 17, 513–24 (2010)

    Article  CAS  Google Scholar 

  28. Y. Shibata, M. Yamazaki, M. Takei, S. Uchino, A. Sakurai, M. Komatsu, Early-onset, severe, and recurrent primary hyperparathyroidism associated with a novel CDC73 mutation. Endocr. J. 62, 627–32 (2015)

    Article  CAS  Google Scholar 

  29. L.F. Starker, T. Akerström, W.D. Long, A. Delgado-Verdugo, P. Donovan, R. Udelsman, R.P. Lifton, T. Carling, Frequent germ-line mutations of the MEN1, CASR, and HRPT2/CDC73 genes in young patients with clinically non-familial primary hyperparathyroidism. Horm. Cancer 3, 44–51 (2012)

    Article  CAS  Google Scholar 

  30. K.J. Bradley, B.M. Cavaco, M.R. Bowl, B. Harding, T. Cranston, C. Fratter, G.M. Besser, M. Conceição Pereira, M.W.J. Davie, N. Dudley, V. Leite, G.P. Sadler, A. Seller, R.V. Thakker, Parafibromin mutations in hereditary hyperparathyroidism syndromes and parathyroid tumours. Clin. Endocrinol. (Oxf.) 64, 299–306 (2006)

    Article  CAS  Google Scholar 

  31. W. Yu, J.R. McPherson, M. Stevenson, R. van Eijk, H.L. Heng, P. Newey, A. Gan, D. Ruano, D. Huang, S.L. Poon, C.K. Ong, T. van Wezel, B. Cavaco, S.G. Rozen, P. Tan, B.T. Teh, R.V. Thakker, H. Morreau, Whole-exome sequencing studies of parathyroid carcinomas reveal novel PRUNE2 mutations, distinctive mutational spectra related to APOBEC-catalyzed DNA mutagenesis and mutational enrichment in kinases associated with cell migration and invasion. J. Clin. Endocrinol. Metab. 100, E360–E364 (2015)

    Article  CAS  Google Scholar 

  32. N. Hatabu, N. Katori, T. Sato, N. Maeda, E. Suzuki, O. Komiyama, H.Tsutsui, T. Nagao, H. Nakauchi-Takahashi, T. Matsunaga, T. Ishii, T. Hasegawa, K. Yamazawa, A Familial Case of a Whole Germline CDC73 Deletion Discordant for Primary Hyperparathyroidism. Horm. Res. Paediatr 92, 56–63 (2019). Epub 8 Feb 2019. https://doi.org/10.1159/000495800

    Article  CAS  PubMed  Google Scholar 

  33. M. Iacobone, G. Masi, L. Barzon, A. Porzionato, V. Macchi, F.A. Ciarleglio, G. Palù, R. De Caro, G. Viel, G. Favia, Hyperparathyroidism–jaw tumor syndrome: a report of three large kindred. Langenbecks Arch. Surg. 394, 817–25 (2009)

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the family for their cooperation. We would also like to thank the Laboratory of Genetics, University Hospital of Lille, and the Laboratory of Anatamopathology, University Hospital of Lille for their cooperation and genetic explorations. We are also grateful to the Laboratory of Pathology, University of Reims, Institute Jean Godinot of Reims, the Department of Nephrology, University Hospital of Reims for their participation and their help. This study was funded by the Department of Endocrinology at the Robert Debre University Hospital of Reims. The authors would like to thank Mrs. Daniela Pellot of the University of Reims for English language proofreading and editing.

Author information

Authors and Affiliations

  1. Department of Endocrinology Diabetology, University of Reims, Reims, France

    Lauriane Le Collen, Sara Barraud & Brigitte Delemer

  2. Inserm/CNRS UMR 1283/8199, Institut Pasteur de Lille, EGID, Lille, France

    Lauriane Le Collen

  3. CRESTIC EA 3804, University of Reims Champagne Ardenne, UFR Sciences Exactes et Naturelles, Moulin de La Housse, BP 1039, 51687, Reims Cedex 2, France

    Sara Barraud & Brigitte Delemer

  4. Department of Nephrology, University of Reims, Reims, France

    Antoine Braconnier

  5. Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER – Cancer - Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France

    Lucie Coppin

  6. Laboratory of Pathology, University of Reims, Reims, France

    Dominique Zachar & Camille Boulagnon

  7. Department of Surgery, University of Reims, Reims, France

    Sophie Deguelte

  8. Department of Pediatrics, University of Reims, Reims, France

    Pierre François Souchon

  9. Department of Genetics, University of Reims, Reims, France

    Marta Spodenkiewicz & Céline Poirsier

  10. Laboratory of Pathology, University of Lille, Lille, France

    Sébastien Aubert

  11. Univ. Lille, Inserm, CHU Lille, U1286 – Infinite – Institute for Translational Research in Inflammation, F-59000, Lille, France

    Marie Françoise Odou

Authors
  1. Lauriane Le Collen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sara Barraud
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antoine Braconnier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lucie Coppin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dominique Zachar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Camille Boulagnon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sophie Deguelte
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pierre François Souchon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marta Spodenkiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Céline Poirsier
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sébastien Aubert
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Marie Françoise Odou
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Brigitte Delemer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Lauriane Le Collen or Brigitte Delemer.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Le Collen, L., Barraud, S., Braconnier, A. et al. A large extended family with hyperparathyroidism-jaw tumor syndrome due to deletion of the third exon of CDC73: clinical and molecular features. Endocrine 73, 693–701 (2021). https://doi.org/10.1007/s12020-021-02756-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-021-02756-4

Keywords

Search

Navigation