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Genotype–phenotype correlation in Juvenile Paget disease: role of molecular alterations of the TNFRSF11B gene

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Abstract

Juvenile Paget disease (JPD) {MIM 239000} is a rare inherited bone disease that affects children. The patients affected with JPD present an altered bone turnover, therefore, show a phenotype characterized by progressive bone deformities, fractures, and short stature. Deletions or missense mutations of the TNFRSN11B gene are common in these children. This gene encodes a soluble protein, the osteoprotegerin, which leads to uncontrolled osteoclastogenesis when mutated. JPD is characterized by a strong genotype–phenotype correlation, so depending on the alteration of the TNFRSN11B gene, the phenotype is variable. This review describes the different clinical features which are characteristic of JPD and the correspondence with the different molecular alterations of the TNFRSN11B gene.

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References

  1. J.A. Kanis, Pathophysiology and Treatment of Paget’s Disease of Bone (Martin Dunitz, London, 1998)

    Google Scholar 

  2. D.J. Hosking, Paget’s disease of bone. BMJ 283, 686–688 (1981)

    Article  PubMed  CAS  Google Scholar 

  3. G.D. Roodman, J.J. Windle, Paget disease of bone. J. Clin. Invest. 115, 200–208 (2005)

    PubMed  CAS  Google Scholar 

  4. A. Rebel, K. Malkani, M. Basle, C. Bregeon, A. Patezour, R. Filmon, Ultrastructural characteristics of osteoclasts in Paget’s disease. Rev. Rhum. Mal. Osteoartic. 41, 767–771 (1974)

    PubMed  CAS  Google Scholar 

  5. S.D. Neale, R. Smith, J.A. Wass, N.A. Athanasou, Osteoclast differentiation from circulating mononuclear precursors in Paget’s disease is hypersensitive to 1,25-dihydroxyvitamin D1 and RANKL. Bone 27, 409–416 (2000)

    Article  PubMed  CAS  Google Scholar 

  6. A. Kukita, C. Chenu, L.M. McManus, G.R. Mundy, G.D. Roodman, Atypical multinucleated cells form in long-term marrow cultures from patients with Paget’s disease. J. Clin. Invest. 85, 1280–1286 (1990)

    Article  PubMed  CAS  Google Scholar 

  7. D. Naot, U. Bava, B. Matthews, K.E. Callon, G.D. Gamble, M. Black, S. Song, R.P. Pitto, T. Cundy, J. Cornish, I.R. Reid, Differential gene expression in cultured osteoblasts and bone marrow stromal cells from patients with Paget’s disease of bone. J. Bone Miner. Res. 22, 298–309 (2007)

    Article  PubMed  CAS  Google Scholar 

  8. A. Demulder, S. Takahashi, F.R. Singer, D.J. Hosking, G.D. Roodman, Abnormalities in osteoclast precursors and marrow accessory cells in Paget’s disease. Endocrinology 133, 1978–1982 (1993)

    Article  PubMed  CAS  Google Scholar 

  9. C. Menaa, S.V. Reddy, N. Kurihara, H. Maeda, D. Anderson, T. Cundy, J. Cornish, F.R. Singer, J.M. Bruder, G.D. Roodman, Enhanced RANK ligand expression and responsivity of bone marrow cells in Paget’s disease of bone. J. Clin. Invest. 105, 1833–1838 (2000)

    Article  PubMed  CAS  Google Scholar 

  10. G. Martini, L. Gennari, D. Merlotti, S. Salvadori, M.B. Franci, S. Campagna, A. Avanzati, V. De Paola, F. Valleggi, R. Nuti, Serum OPG and RANKL levels before and after intravenous bisphosphonate treatment in Paget’s disease of bone. Bone 40, 457–463 (2007)

    Article  PubMed  CAS  Google Scholar 

  11. S. Seitz, M. Priemel, J. Zustin, F.T. Beil, J. Semler, H. Minne, T. Schinke, M. Amling, Paget’s disease of bone: histologic analysis of 754 patients. J. Bone Miner. Res. 24, 62–69 (2009)

    Article  PubMed  Google Scholar 

  12. P.L. Selby, M.W. Davie, S.H. Ralston, M.D. Stone, Bone and Tooth Society of Great Britain, National Association for the Relief of Paget’s Disease, Guidelines on the management of Paget’s disease of bone. Bone 31, 366–373 (2002)

    Article  PubMed  CAS  Google Scholar 

  13. A.T. Deyrup, A.G. Montag, C.Y. Inwards, Z. Xu, R.G. Swee, U.K. Krishnan, Sarcomas arising in Paget disease of bone: a clinicopathologic analysis of 70 cases. Arch. Pathol. Lab. Med. 131, 942–946 (2007)

    PubMed  Google Scholar 

  14. M.F. Hansen, M.J. Nellissery, P. Bhatia, Common mechanisms of osteosarcoma and Paget’s disease. J. Bone Miner. Res. 14, 39–44 (1999)

    Article  PubMed  Google Scholar 

  15. H.J. Mankin, F.J. Hornicek, Paget’s sarcoma: a historical and outcome review. Clin. Orthop. Relat. Res. 438, 97–102 (2005)

    Article  PubMed  Google Scholar 

  16. D.J. Barker, M.J. Gardner, Distribution of Paget’s disease in England, Wales and Scotland and a possible relationship with vitamin D deficiency in childhood. Br. J. Prev. Soc. Med. 28, 226–232 (1974)

    PubMed  CAS  Google Scholar 

  17. E.S. Siris, Epidemiological aspects of Paget’s disease: family history and relationship to other medical conditions. Semin. Arthritis Rheum. 23, 222–225 (1994)

    Article  PubMed  CAS  Google Scholar 

  18. G. Lopez-Abente, A. Morales-Piga, A. Elena-Ibanez, J.S. Rey–Rey, J. Corres-Gonzalez, Cattle, pets, and Paget’s disease of bone. Epidemiology 8, 247–251 (1997)

    Article  PubMed  CAS  Google Scholar 

  19. E.S. Siris, Seeking the elusive aetiology of Paget’s disease: a progress report. J. Bone Miner. Res. 11, 1599–1601 (1996)

    Article  PubMed  CAS  Google Scholar 

  20. J.H. Lever, Paget’s disease of bone in Lancashire and arsenic pesticide in cotton mill wastewater: a speculative hypothesis. Bone 31, 434–436 (2002)

    Article  PubMed  CAS  Google Scholar 

  21. M.T. Gordon, D.C. Anderson, P.T. Sharpe, Canine distemper virus localised in bone cells of patients with Paget’s disease. Bone 12, 195–201 (1991)

    Article  PubMed  CAS  Google Scholar 

  22. M.H. Helfrich, R.P. Hobson, P.S. Grabowski, A. Zurbriggen, S.L. Cosby, G.R. Dickson, W.D. Fraser, C.G. Ooi, P.L. Selby, A.J. Crisp, R.G. Wallace, S. Kahn, S.H. Ralston, A negative search for a paramyxoviral etiology of Paget’s disease of bone: molecular, immunological, and ultrastructural studies in UK patients. J. Bone Miner. Res. 15, 2315–2329 (2000)

    Article  PubMed  CAS  Google Scholar 

  23. C.G. Ooi, C.A. Walsh, J.A. Gallagher, W.D. Fraser, Absence of measles virus and canine distemper virus transcripts in long-term bone marrow cultures from patients with Paget’s disease of bone. Bone 27, 417–421 (2000)

    Article  PubMed  CAS  Google Scholar 

  24. S.V. Reddy, F.R. Singer, G.D. Roodman, Bone marrow mononuclear cells from patients with Paget’s disease contain measles virus nucleocapsid messenger ribonucleic acid that has mutations in a specific region of the sequence. J. Clin. Endocrinol. Metab. 80, 2108–2111 (1995)

    Article  PubMed  CAS  Google Scholar 

  25. A. Falchetti, F. Marini, L. Masi, A. Amedei, M.L. Brandi, Genetic aspects of the Paget’s disease of bone: concerns on the introduction of DNA-based tests in the clinical practice. Advantages and disadvantages of its application. Eur. J. Clin. Invest. 40, 655–667 (2010)

    Article  PubMed  CAS  Google Scholar 

  26. L. Gennari, F. Gianfrancesco, M. Di Stefano, D. Rendina, D. Merlotti, T. Esposito, S. Gallone, P. Fusco, I. Rainero, P. Fenoglio, M. Mancini, G. Martini, S. Bergui, G. De Filippo, G. Isaia, P. Strazzullo, R. Nuti, G. Mossetti, SQSTM1 gene analysis and gene-environment interaction in Paget’s disease of bone. J. Bone Miner. Res. 25, 1375–1384 (2010)

    Article  PubMed  CAS  Google Scholar 

  27. M.H. Helfrich, L.J. Hocking, Genetics and aetiology of Pagetic disorders of bone. Arch. Biochem. Biophys. 473, 172–182 (2008)

    Article  PubMed  CAS  Google Scholar 

  28. G.J. Lucas, A. Daroszewska, S.H. Ralston, Contribution of genetic factors to the pathogenesis of Paget’s disease of bone and related disorders. J. Bone Miner. Res. 21, 31–37 (2006)

    Article  Google Scholar 

  29. P.H. Osterberg, R.G. Wallace, D.A. Adams, R.S. Crone, G.R. Dickson, J.A. Kanis, R.A. Mollan, N.C. Nevin, J. Sloan, P.G. Toner, Familial expansile osteolysis. A new dysplasia. J. Bone Joint Surg. Br. 70, 255–260 (1988)

    PubMed  CAS  Google Scholar 

  30. M.P. Whyte, B.G. Mills, W.R. Reinus, M.N. Podgornik, G.D. Roodman, F.H. Gannon, M.C. Eddy, W.H. McAlister, Expansile skeletal hyperphosphatasia: a new familial metabolic bone disease. J. Bone Miner. Res. 15, 2330–2344 (2000)

    Article  PubMed  CAS  Google Scholar 

  31. K. Nakatsuka, Y. Nishizawa, S.H. Ralston, Phenotypic characterization of early onset Paget’s disease of bone caused by a 27-bp duplication in the TNFRSF11A gene. J. Bone Miner. Res. 18, 1381–1385 (2003)

    Article  PubMed  CAS  Google Scholar 

  32. M.P. Whyte, S.E. Obrecht, P.M. Finnegan, J.L. Jones, M.N. Podgornik, W.H. McAlister, S. Mumm, Osteoprotegerin deficiency and juvenile Paget’s disease. N. Engl. J. Med. 347, 175–184 (2002)

    Article  PubMed  CAS  Google Scholar 

  33. M.J. Kovach, B. Waggoner, S.M. Leal, D. Gelber, R. Khardori, M.A. Levenstien, C.A. Shanks, G. Gregg, M.T. Al Lozi, T. Miller, W. Rakowicz, G. Lopate, J. Florence, G. Glosser, Z. Simmons, J.C. Morris, M.P. Whyte, A. Pestronk, V.E. Kimonis, Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Mol. Genet. Metab. 74, 458–475 (2001)

    Article  PubMed  CAS  Google Scholar 

  34. O. Blanco, M. Stivel, C. Mautalen, F. Schajowicz, Familial idiopathic hyperphosphatasia: a study of two young siblings treated with porcine calcitonin. J. Bone Joint Surg. Br. 59, 421–427 (1977)

    PubMed  Google Scholar 

  35. D.S. Golob, W.H. McAlister, B.G. Mills, K.N. Fedde, W.R. Reinus, S.L. Teitelbaum, S. Beeki, M.P. Whyte, Juvenile Paget disease: life-long features of a mildly affected young woman. J. Bone Miner. Res. 11, 132–142 (1996)

    Article  PubMed  CAS  Google Scholar 

  36. R.C. Thompson Jr, G.E. Gaul, S.J. Horowitz, R.K. Schenk, Hereditary hyperphosphatasia. Studies of three siblings. Am. J. Med. 47, 209–219 (1969)

    Article  PubMed  Google Scholar 

  37. J. Caffey, Familial hyperphosphatasemia with ateliosis and hypermetabolism of growing membranous bone; review of the clinical, radiographic and chemical features. Bull. Hosp. Jt. Dis. 33, 81–110 (1972)

    CAS  Google Scholar 

  38. S. Jett, H.M. Frost, Tetracycline-based measurements of the bone dynamics in the rib of a girl with hyperphosphatasia. Henry Ford Hosp. Med. J. 16, 325–338 (1968)

    PubMed  CAS  Google Scholar 

  39. S.M. Mitsudo, Chronic idiopathic hyperphosphatasia associated with pseudoxanthonia elasticurn. J. Bone Joint Surg. Am. 53, 303–314 (1971)

    PubMed  CAS  Google Scholar 

  40. M.P. Desai, N.C. Joshi, K.N. Shah, Chronic idiopathic hyperphosphatasia in an Indian child. Am. J. Dis. Child. 126, 626–628 (1973)

    PubMed  CAS  Google Scholar 

  41. M.T. Duillo, A. Pelizza, G. Caramia, Chronic idiopathic hyperphosphatasia: a case with malabsorption syndrome. Panminerva Med. 19, 53–64 (1977)

    PubMed  CAS  Google Scholar 

  42. E.J. Eyring, E. Eisenberg, Congenital hyperphosphatasia. A clinical, pathological, and biochemical study of two cases. J. Bone Joint Surg. Am. 50, 1099–1117 (1968)

    PubMed  CAS  Google Scholar 

  43. G.N. Stemmermann, An histologic and histochemical study of familial osteoectasia. (Chronic idiopathic hyperphosphatasia). Am. J. Pathol. 48, 641–651 (1966)

    PubMed  CAS  Google Scholar 

  44. V. Dunn, V.R. Condon, M.L. Rallison, Familial hyperphosphatasemia: diagnosis in early infancy and response to human thyrocalcitonin therapy. AJR Am. J. Roentgenol. 132, 541–545 (1979)

    PubMed  CAS  Google Scholar 

  45. T.A. Einhorn, V.J. Vigorita, J.B. Teitcher, Hyperphosphatasemia in an adult. Clinical, roentgenographic, and histomorphometric findings and comparison to classical Paget’s disease. Clin. Orthop. Relat. Res. 204, 253–260 (1986)

    PubMed  Google Scholar 

  46. M. Eroglu, N.N. Taneli, Congenital hyperphosphatasia (juvenile Paget’s disease). Eleven years follow-up of three sisters. Ann. Radiol. 20, 145–150 (1977)

    PubMed  CAS  Google Scholar 

  47. T.C. Iancu, G. Almagor, E. Friedman, R. Hardoff, D. Front, Chronic familial hyperphosphatasemia. Radiology 129, 669–676 (1978)

    PubMed  CAS  Google Scholar 

  48. B. Chong, M. Hedge, M. Fawkner, S. Simonet, H. Cassinelli, M. Coker, J. Kanis, J. Seidel, C. Tau, B. Tuysuz, B. Yuksel, D. Love, T. Cundy, Idiopathic hypershosphatasia and TNFRSF11B mutations: relationships between phenotype and genotype. J. Bone Miner. Res. 18, 2095–2104 (2003)

    Article  PubMed  CAS  Google Scholar 

  49. T. Cundy, M. Hegde, D. Naot, B. Chong, A. King, R. Wallace, J. Mulley, D.R. Love, J. Seidel, M. Fawkner, T. Banovic, K.E. Callon, A.B. Grey, I.R. Reid, C.A. Middleton-Hardie, J. Cornish, A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Hum. Mol. Genet. 11, 2119–2127 (2002)

    Article  PubMed  CAS  Google Scholar 

  50. W.J. Boyle, W.S. Simonet, D.L. Lacey, Osteoclast differentiation and activation. Nature 423, 337–342 (2003)

    Article  PubMed  CAS  Google Scholar 

  51. N. Bucay, I. Sarosi, C.R. Dunstan, S. Morony, J. Tarpley, C. Capparelli, S. Scully, H.L. Tan, W. Xu, D.L. Lacey, W.J. Boyle, W.S. Simonet, Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 12, 1260–1268 (1998)

    Article  PubMed  CAS  Google Scholar 

  52. W.S. Simonet, D.L. Lacey, C.R. Dunstan, M. Kelley, M.S. Chang, R. Lüthy, H.Q. Nguyen, S. Wooden, L. Bennett, T. Boone, G. Shimamoto, M. DeRose, R. Elliott, A. Colombero, H.L. Tan, G. Trail, J. Sullivan, E. Davy, N. Bucay, L. Renshaw-Gegg, T.M. Hughes, D. Hill, W. Pattison, P. Campbell, S. Sander, G. Van, J. Tarpley, P. Derby, R. Lee, W.J. Boyle, Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309–319 (1997)

    Article  PubMed  CAS  Google Scholar 

  53. M.P. Whyte, Paget’s disease of bone and genetic disorders of RANKL/OPG/RANK/NF-kappaB signalling. Ann. NY. Acad. Sci. 1068, 143–164 (2006)

    Article  PubMed  CAS  Google Scholar 

  54. C. Middleton-Hardie, Q. Zhu, H. Cundy, J.M. Lin, K. Callon, P.C. Tong, J. Xu, A. Grey, J. Cornish, D. Naot, Deletion of aspartate 182 in OPG causes juvenile Paget’s disease by impairing both protein secretion and binding to RANKL. J. Bone Miner. Res. 21, 438–445 (2006)

    Article  PubMed  CAS  Google Scholar 

  55. K. Janssens, M.C. de Vernejoul, F. de Freitas, F. Vanhoenacker, W. Van Hul, An intermediate form of juvenile Paget’s disease caused by a truncating TNFRSF11B mutation. Bone 36, 542–548 (2005)

    Article  PubMed  CAS  Google Scholar 

  56. T. Cundy, J. Davidson, M.D. Rutland, C. Stewart, A.M. DePaoli, Recombinant osteoprotegerin for juvenile Paget’s disease. N. Engl. J. Med. 353, 918–923 (2005)

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Basic Medical Sciences, Section of Human Anatomy and Histology, University of Bari, Bari, Italy

    Giacomina Brunetti, Silvia Colucci & Maria Grano

  2. Interdisciplinary Department of Medicine, University of Bari, Piazza G. Cesare, 11, 70100, Bari, Italy

    Flaviana Marzano, Annamaria Ventura, Luciano Cavallo & Maria Felicia Faienza

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  1. Giacomina Brunetti
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  2. Flaviana Marzano
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Correspondence to Maria Felicia Faienza.

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Brunetti, G., Marzano, F., Colucci, S. et al. Genotype–phenotype correlation in Juvenile Paget disease: role of molecular alterations of the TNFRSF11B gene. Endocrine 42, 266–271 (2012). https://doi.org/10.1007/s12020-012-9705-0

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