# 167250

PAGET DISEASE OF BONE 3; PDB3


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
5q35.3 Paget disease of bone 3 167250 AD 3 SQSTM1 601530
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal dominant
HEAD & NECK
Ears
- Deafness (in some patients)
SKELETAL
- Increased and disorganized bone remodeling
- Mixed regions of osteosclerosis and osteolysis
- Abnormal uptake of radio-labelled bisphosphates in affected sites on bone scan
- Bone pain
- Deformity or enlargement of bones
- Osteoarthrosis
- Increased risk of fractures
LABORATORY ABNORMALITIES
- Increased alkaline phosphatase
MISCELLANEOUS
- Onset usually after age 40
- Incomplete age-dependent penetrance
- Axial skeleton most commonly affected
MOLECULAR BASIS
- Caused by mutation in the sequestosome 1 gene (SQSTM1, 601530.0001)

TEXT

A number sign (#) is used with this entry because of evidence that Paget disease of bone-3 (PDB3) is caused by heterozygous mutation in the SQSTM1 gene (601530) on chromosome 5q35.


Description

Paget disease is a metabolic bone disease characterized by focal abnormalities of increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Bone lesions in this disorder show evidence of increased osteoclastic bone resorption and disorganized bone structure. See reviews by Ralston et al. (2008) and Ralston and Albagha (2014).

Genetic Heterogeneity of Paget Disease of Bone

Also see PDB2 (602080), caused by mutation in the TNFRSF11A gene (603499) on chromosome 18q21; PDB4 (606263), mapped to chromosome 5q31; PDB5 (239000), caused by mutation in the TNFRSF11B gene (602643) on chromosome 8q24; and PDB6 (616833), caused by mutation in the ZNF687 gene (610568) on chromosome 1q21.

Suggestive linkage of a form of PDB to chromosome 6p (PDB1) was reported by Fotino et al. (1977); however, further studies did not confirm linkage to this site (Moore and Hoffman, 1988; Nance et al., 2000; Good et al., 2001).


Clinical Features

Paget disease of bone usually occurs in persons over the age of 40 years (Klein and Norman, 1995) and mainly affects the axial skeleton. Approximately 5% of patients present symptoms requiring treatment, the most frequent complaints being bone pain, enlargement, and deformities at the pagetic site (Kanis, 1998). Other manifestations of the disease include increased susceptibility to fractures, deafness, and neurologic complications (Hamdy, 1995).

In 5 patients with ancestry in southern Italy, Jacobs et al. (1979) described giant cell tumor as a complication of Paget disease of bone. Three of the patients were related. High doses of dexamethasone resulted in dramatic shrinking of tumors. Wu et al. (1991) reported 2 sisters and a brother with longstanding (35 years in 1) polyostotic Paget disease. Two of them developed osteogenic sarcoma at sites unrelated to surgical procedures, one in the sacrum and one in the calvaria. Both died shortly after diagnosis of malignancy because of aggressive spread of the tumor. The 3 sibs came from Castallamarre, Italy, which is approximately 10 km from Avellino where the ancestors of the patients of Jacobs et al. (1979) lived.


Inheritance

Reports of familial aggregation of Paget disease of bone are rather numerous, including occurrence in successive generations. McKusick (1960) reviewed 35 pedigrees reported to 1956 and added 2 others. In only 1 family, that of van Bogaert (1933), was there male-to-male transmission. In this family, all affected members and some unaffected members had retinitis pigmentosa, which may have been an independent, i.e., coincidental, genetic disorder.

Jones and Reed (1967) observed 6 cases in 3 generations of a family. Evens and Bartter (1968) described 7 definite and 2 probable cases in 1 kindred.

Leach et al. (2001) reviewed Paget disease, noting that in a study of the frequency and characteristics of the familial aggregation of PDB in Spain, Morales-Piga et al. (1995) found that 40% of their index cases had at least 1 first-degree relative affected with PDB. In the pedigrees they reported, PDB seemed to be transmitted through either parent, suggesting an autosomal dominant mode of inheritance.

Siris (1994) conducted an epidemiologic study of PDB in the United States, using questionnaires completed by 864 patients with physician-diagnosed PDB, and compared these results to 500 controls of similar age. A history of PDB was noted in a first-degree relative in 12% of the patients, compared with only 2% of controls. The risk of first-degree relatives of a PDB patient developing PDB was 7 times greater than for an individual without an affected relative. The cumulative risk for developing PDB up to age 90 for a first-degree relative of a patient was 9% compared with 2% in individuals with unaffected relatives. The authors concluded that these data are good evidence that genetics plays a role in the acquisition of the disease.


Pathogenesis

See 147620 for evidence that interleukin-6 is involved in the hyperplasia and hypertrophy of osteoclasts in Paget disease.

In addition to the genetic etiology of Paget disease, electron microscopic demonstration of virus-like bodies in bone cells of patients with Paget disease suggests a viral etiology (Mills and Singer, 1976). Winfield and Sutherland (1981) could find no serologic support for the suggestion of Rebel et al. (1976) that the inclusions represent measles virus. In all 25 biopsies showing histologic evidence of Paget disease, derived from 22 patients, electron microscopy showed characteristic nuclear and cytoplasmic inclusions in the osteoclasts (Harvey et al., 1982). Osteocytes, osteoblasts, hematopoietic cells and connective tissue cells lacked inclusions. The intranuclear inclusions consisted of stacked rows or complex whorls of tubular filaments, each of 12 to 15 mm diameter, often arranged in a paracrystalline array. The frequency of occurrence of inclusions in osteoclasts and in their individual nuclei correlated with the histologic severity of the disease process. The similarity of the inclusions to paramyxovirus inclusion bodies (particularly those of measles) supported, in the view of the authors, the hypothesis that Paget disease is a slow virus infection.

Concentration of cases in Lancashire, England (Barker et al., 1980) and in Australia (Gardner et al., 1978) suggests an important environmental factor in etiology.

Cody et al. (1997) noted similarities between Paget disease and familial expansile osteolysis (FEO; 174810). The histologic bone lesions of FEO appeared to be similar to pagetic lesions, although they occurred at a much earlier age and were more severe. Furthermore, as in Paget disease, the osteoclasts in patients with FEO contain paramyxoviral-like nuclear inclusions. Cody et al. (1997) reviewed the evidence suggesting a viral etiology of Paget disease.


Clinical Management

Singer et al. (1998) treated 13 patients with severe Paget disease of bone (mean serum alkaline phosphatase level 17 times the upper limit of normal) with 30 mg oral risedronate daily for 8 weeks. All patients who completed the study had a decrease in serum alkaline phosphatase levels of at least 77% from the baseline. Oral risedronate was well tolerated by the patients. Only 1 patient discontinued treatment because of an adverse event (diarrhea) thought to be related to risedronate therapy.

Noor and Shoback (2000) stated that therapy with bisphosphonate drugs is the treatment of choice.


Mapping

Laurin et al. (2001) performed genetic linkage analysis in 24 large French Canadian families (479 individuals) in which Paget disease was segregating as an autosomal dominant trait. After excluding linkage to the PDB2 locus (602080), they performed a genomewide scan on the 3 most informative family nuclei. Lod scores greater than 1.0 were found at 7 locations. The disorder in 8 of the families showed strong linkage to chromosome 5q35-qter, and the disease locus was designated PDB3. Under heterogeneity, a maximum lod score of 8.58 was obtained at D5S2073 at theta = 0.10. The same characteristic haplotype was carried by all patients in the 8 families, suggesting a founder effect. A recombination event in a key family confined the disease region within a 6-cM interval between D5S469 and the telomere. The disorder in the 16 other families, with very low conditional probability of linkage to 5q35-qter, showed linkage to 5q31 (PDB4; 606263).

Hocking et al. (2001) conducted a genomewide search in 319 individuals from 62 kindreds with familial PDB who were predominantly of British descent. The pattern of inheritance in the study group as a whole was consistent with autosomal dominant transmission of the disease. Parametric multipoint linkage analysis, under a model of heterogeneity, identified 3 chromosomal regions with lod scores above the thresholds for suggestive linkage. These included 5q35; maximum lod score of 3.0 at 189.63 cM between markers D5S400 and D5S408. Two-point linkage analysis with a series of markers from the 5q35 region in another large kindred with autosomal dominant familial PDB also supported linkage to the candidate region with a maximum lod score of 3.47 at D5S2034 (187.8 cM). These data indicated the presence of several susceptibility loci for PDB and identified a strong candidate locus for the disease on 5q35.


Heterogeneity

Nance et al. (2000) reported the identification and clinical characterization of a large pedigree with Paget disease in which the disorder was not linked to the 18q region, thus confirming genetic heterogeneity. The disorder in this pedigree was clinically indistinguishable from Paget disease linked to chromosome 18 and differed from sporadic Paget disease only in a lower age of onset in some affected individuals.

Associations Pending Confirmation

In a genomewide search in 319 individuals from 62 kindreds, predominantly of British descent, with familial PDB, Hocking et al. (2001) identified 3 chromosomal regions with lod scores above the threshold for suggestive linkage. These were on chromosomes 2q36 (lod score 2.7 at 218.24 cM), 5q35 (lod score 3.0 at 189.63 cM), and 10p13 (lod score 2.6 at 41.43 cM). For each of these loci, formal heterogeneity testing with HOMOG supported a model of linkage with heterogeneity, as opposed to no linkage or linkage with homogeneity.

In a large pedigree with PDB, Good et al. (2001) found significantly low lod scores for linkage at the PDB1 and PDB2 loci. In 1 branch of this family, a 'subpedigree' that showed a significantly lower age at diagnosis than the rest of the pedigree, Good et al. (2002) found linkage to 18q23 (maximum 2-point lod score of 4.23 at theta = 0.0 with marker D18S1390). Good et al. (2002) found no mutations in exon 1 of the TNFRSF11A gene in affected members of the subpedigree.

Albagha et al. (2010) performed a genomewide association study in 750 individuals with PDB without SQSTM1 mutation in 1,002 controls and identified 3 candidate disease loci that were then replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 near the CSF1 gene (120420) (p = 5.38 x 10(-24)). A significant association was also observed with rs1561570 on 10p13 within the OPTN gene (602432) (p = 6.09 x 10(-13)). Albagha et al. (2010) also confirmed linkage with PDB of a region on chromosome 18q21 near the TNFRSF11A gene, represented by rs3018362 (p = 5.27 x 10(-13)).

Albagha et al. (2011) extended their previous study of PDB and identified 3 new loci, confirming their association with PDB in 2,215 affected individuals (cases) and 4,370 controls from 7 different populations. The new associations were with rs5742915 within PML (102578) on chromosome 15q24 (odds ratio = 1.34, p = 1.6 x 10(-14)), rs10498635 within RIN3 (610223) on chromosome 14q32 (odds ratio = 1.44, p = 2.55 x 10(-11)), and rs4294134 within NUP205 (614352) on chromosome 7q33 (odds ratio = 1.45, p = 8.45 x 10(-10)). Albagha et al. (2011) stated that their data also confirmed the association with TM7SF4 (605933) on chromosome 8q22 (rs2458413, odds ratio = 1.40, p = 7.38 x 10(-17)) with PDB. These 7 loci explained approximately 13% of the familial risk of PDB.


Molecular Genetics

By screening for mutations in the SQSTM1 gene in French Canadian families with Paget disease of bone mapping to 5q35-qter, Laurin et al. (2002) identified a recurrent heterozygous nonconservative missense mutation (P392L; 601530.0001) on 2 different haplotypes defined by intragenic SNPs. The mutation occurred at a hypermutable CpG dinucleotide, suggesting that it arose by deamination of a methylated cytosine. The mutation was not present in 291 control individuals.

In affected members of 4 families with Paget disease of bone, Hocking et al. (2002) identified a heterozygous 1-bp insertion (c.1224insT; 601530.0002) in the SQSTM1 gene.

In affected members of an Australian family with Paget disease of bone, Hocking et al. (2002) identified a splice site mutation in the SQSTM1 gene (601530.0003).


History

Paget (1877) first described this localized skeletal disease as osteitis deformans.

Fotino et al. (1977) found possible linkage of PDB to the HLA region of chromosome 6p, but the lod score of 2.44 did not reach the usually accepted level of proof. Moore and Hoffman (1988) could not demonstrate linkage with MHC in a 2-generation family. Nance et al. (2000) and Good et al. (2001) found no linkage of PDB with chromosome 6p.


REFERENCES

  1. Albagha, O. M. E., Visconti, M. R., Alonso, N., Langston, A. L., Cundy, T., Dargie, R., Dunlop, M. G., Fraser, W. D., Hooper, M. J., Isaia, G., Nicholson, G. C., Montes, J. P., Gonzalez-Sarmiento, R., di Stefano, M., Tenesa, A., Walsh, J. P., Ralston, S. H. Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone. Nature Genet. 42: 520-524, 2010. [PubMed: 20436471, images, related citations] [Full Text]

  2. Albagha, O. M. E., Wani, S. E., Visconti, M. R., Alonso, N., Goodman, K., Brandi, M. L., Cundy, T., Chung, P. Y. J., Dargie, R., Devogelaer, J.-P., Falchetti, A., Fraser, W. D., and 17 others. Genome-wide association identifies three new susceptibility loci for Paget's disease of bone. Nature Genet. 43: 685-689, 2011. [PubMed: 21623375, related citations] [Full Text]

  3. Barker, D. J. P., Chamberlain, A. T., Guyer, P. B., Gardner, M. J. Paget's disease of bone: the Lancashire focus. Brit. Med. J. 280: 1105-1107, 1980. [PubMed: 7388425, related citations] [Full Text]

  4. Cody, J. D., Singer, F. R., Roodman, G. D., Otterund, B., Lewis, T. B., Leppert, M., Leach, R. J. Genetic linkage of Paget disease of the bone to chromosome 18q. Am. J. Hum. Genet. 61: 1117-1122, 1997. [PubMed: 9345096, related citations] [Full Text]

  5. Evens, R. G., Bartter, F. C. The hereditary aspects of Paget's disease (osteitis deformans). JAMA 205: 900-902, 1968. [PubMed: 5695397, related citations]

  6. Fotino, M., Haymovits, A., Falk, C. T. Evidence for linkage between HLA and Paget's disease. Transplant. Proc. 9: 1867-1868, 1977. [PubMed: 146288, related citations]

  7. Gardner, M. J., Guyer, P. B., Barker, D. J. P. Radiological prevalence of Paget's disease of bone in British migrants to Australia. Brit. Med. J. 1: 1655-1657, 1978. [PubMed: 656864, related citations] [Full Text]

  8. Good, D. A., Busfield, F., Fletcher, B. H., Duffy, D. L., Kesting, J. B., Andersen, J., Shaw, J. T. E. Linkage of Paget disease of bone to a novel region on human chromosome 18q23. Am. J. Hum. Genet. 70: 517-525, 2002. [PubMed: 11742440, images, related citations] [Full Text]

  9. Good, D., Busfield, F., Duffy, D., Lovelock, P. K., Kesting, J. B., Cameron, D. P., Shaw, J. T. E. Familial Paget's disease of bone: nonlinkage to the PDB1 and PDB2 loci on chromosomes 6p and 18q in a large pedigree. J. Bone Miner. Res. 16: 33-38, 2001. [PubMed: 11149487, related citations] [Full Text]

  10. Hamdy, R. C. Clinical features and pharmacologic treatment of Paget's disease. Endocr. Metab. Clin. North Am. 24: 421-436, 1995. [PubMed: 7656897, related citations]

  11. Harvey, L., Gray, T., Beneton, M. N. C., Douglas, D. L., Kanis, J. A., Russell, R. G. G. Ultrastructural features of the osteoclasts from Paget's disease of bone in relation to a viral aetiology. J. Clin. Path. 35: 771-779, 1982. [PubMed: 7096600, related citations] [Full Text]

  12. Haslam, S. I., Van Hul, W., Morales-Piga, A., Balemans, W., San-Millan, J. L., Nakatsuka, K., Willems, P., Haites, N. E., Ralston, S. H. Paget's disease of bone: evidence for a susceptibility locus on chromosome 18q and for genetic heterogeneity. J. Bone Miner. Res. 13: 911-917, 1998. [PubMed: 9626621, related citations] [Full Text]

  13. Hocking, L. J., Herbert, C. A., Nicholls, R. K., Williams, F., Bennett, S. T., Cundy, T., Nicholson, G. C., Wuyts, W., Van Hul, W., Ralston, S. H. Genomewide search in familial Paget disease of bone shows evidence of genetic heterogeneity with candidate loci on chromosomes 2q36, 10p13, and 5q35. Am. J. Hum. Genet. 69: 1055-1061, 2001. [PubMed: 11555792, images, related citations] [Full Text]

  14. Hocking, L. J., Lucas, G. J. A., Daroszewska, A., Mangion, J., Olavesen, M., Cundy, T., Nicholson, G. C., Ward, L., Bennett, S. T., Wuyts, W., Van Hul, W., Ralston, S. H. Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Hum. Molec. Genet. 11: 2735-2739, 2002. [PubMed: 12374763, related citations] [Full Text]

  15. Jacobs, T. P., Michelsen, J., Polay, J. S., D'Adamo, A. C., Canfield, R. E. Giant cell tumor in Paget's disease of bone: familial and geographic clustering. Cancer 44: 742-747, 1979. [PubMed: 476580, related citations] [Full Text]

  16. Jones, J. V., Reed, M. F. Paget's disease: a family with six cases. Brit. Med. J. 4: 90-91, 1967. [PubMed: 6047851, related citations] [Full Text]

  17. Kanis, J. A. Pathophysiology and Treatment of Paget's Disease of Bone. (2nd ed.) London: Martin Dunitz (pub.) 1998.

  18. Klein, R. M., Norman, A. Diagnostic procedures for Paget's disease: radiologic, pathologic, and laboratory testing. Endocr. Metab. Clin. North Am. 24: 437-450, 1995. [PubMed: 7656898, related citations]

  19. Laurin, N., Brown, J. P., Lemainque, A., Duchesne, A., Huot, D., Lacourciere, Y., Drapeau, G., Verreault, J., Raymond, V., Morissette, J. Paget disease of bone: mapping at loci at 5q35-qter and 5q31. Am. J. Hum. Genet. 69: 528-543, 2001. [PubMed: 11473345, images, related citations] [Full Text]

  20. Laurin, N., Brown, J. P., Morissette, J., Raymond, V. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am. J. Hum. Genet. 70: 1582-1588, 2002. [PubMed: 11992264, images, related citations] [Full Text]

  21. Leach, R. J., Singer, F. R., Roodman, G. D. Genetics of endocrine disease: the genetics of Paget's disease of the bone. J. Clin. Endocr. Metab. 86: 24-28, 2001. [PubMed: 11231972, related citations] [Full Text]

  22. McKusick, V. A. Paget's disease of the bone. Heritable Disorders of Connective Tissue. (3rd ed.) St. Louis: C. V. Mosby (pub.) 1960. Pp. 718-723.

  23. Mills, B. G., Singer, F. R. Nuclear inclusions in Paget's disease of bone. Science 194: 201-202, 1976. [PubMed: 959849, related citations] [Full Text]

  24. Montagu, M. F. A. Paget's disease (osteitis deformans) and heredity. Am. J. Hum. Genet. 1: 94-95, 1949. [PubMed: 17948387, related citations]

  25. Moore, S. B., Hoffman, D. L. Absence of HLA linkage in a family with osteitis deformans (Paget's disease of bone). Tissue Antigens 31: 69-70, 1988. [PubMed: 3163858, related citations] [Full Text]

  26. Morales-Piga, A. A., Rey-Rey, J. S., Corres-Gonzalez, J., Garcia-Sagredo, J. M., Lopez-Abente, G. Frequency and characteristics of familial aggregation of Paget's disease of bone. J. Bone Miner. Res. 10: 663-670, 1995. [PubMed: 7610939, related citations] [Full Text]

  27. Nance, M. A., Nuttall, F. Q., Econs, M. J., Lyles, K. W., Viles, K. D., Vance, J. M., Pericak-Vance, M. A., Speer, M. C. Heterogeneity in Paget disease of the bone. Am. J. Med. Genet. 92: 303-307, 2000. [PubMed: 10861657, related citations] [Full Text]

  28. Noor, M., Shoback, D. Paget's disease of bone: diagnosis and treatment update. Curr. Rheum. Rep. 2: 67-73, 2000. [PubMed: 11123042, related citations] [Full Text]

  29. Paget, J. On a form of chronic inflammation of bones (osteitis deformans). Med. Chir. Trans. 60: 37-63, 1877. [PubMed: 20896492, related citations] [Full Text]

  30. Ralston, S. H., Albagha, O. M. E. Genetics of Paget's disease of bone. Curr. Osteoporos. Rep. 12: 263-271, 2014. [PubMed: 24988994, related citations] [Full Text]

  31. Ralston, S. H., Langston, A. L., Reid, I. R. Pathogenesis and management of Paget's disease of bone. Lancet 372: 155-163, 2008. [PubMed: 18620951, related citations] [Full Text]

  32. Rebel, A., Malkani, K., Basle, M., Bregeon, C. Osteoclast ultrastructure in Paget's disease. Calcif. Tissue Res. April: 187-199, 1976. [PubMed: 177153, related citations] [Full Text]

  33. Singer, F. R., Clemens, T. L., Eusebio, R. A., Bekker, P. J. Risedronate, a highly effective oral agent in the treatment of patients with severe Paget's disease. J. Clin. Endocr. Metab. 83: 1906-1910, 1998. [PubMed: 9626117, related citations] [Full Text]

  34. Siris, E. S. Epidemiological aspects of Paget's disease: family history and relationship to other medical conditions. Semin. Arthritis Rheum. 23: 222-225, 1994. [PubMed: 8009230, related citations] [Full Text]

  35. Sofaer, J. A., Holloway, S. M., Emery, A. E. H. A family study of Paget's disease of bone. J. Epidemiol. Community Health 37: 226-231, 1983. [PubMed: 6619722, related citations] [Full Text]

  36. Van Bogaert, L. Ueber eine hereditaere und familiaere Form der Pagetschen ostitis deformans mit Chorioretinitis pigmentosa. Z. Ges. Neurol. Psychiat. 147: 327-345, 1933.

  37. Winfield, J., Sutherland, S. Measles antibody in Paget's disease. (Letter) Lancet 317: 891 only, 1981. Note: Originally Volume I. [PubMed: 6112310, related citations] [Full Text]

  38. Wu, R. K., Trumble, T. E., Ruwe, P. A. Familial incidence of Paget's disease and secondary osteogenic sarcoma: a report of three cases from a single family. Clin. Orthop. Rel. Res. 265: 306-309, 1991.


Carol A. Bocchini - updated : 7/1/2015
Victor A. McKusick - updated : 6/7/2000
John A. Phillips, III - updated : 9/29/1998
Victor A. McKusick - updated : 10/23/1997
Creation Date:
Victor A. McKusick : 6/2/1986
carol : 10/20/2021
carol : 10/19/2021
carol : 07/09/2016
alopez : 6/13/2016
alopez : 2/26/2016
ckniffin : 2/25/2016
carol : 1/30/2016
carol : 7/22/2015
carol : 7/1/2015
carol : 6/30/2015
carol : 9/13/2001
carol : 6/9/2000
terry : 6/7/2000
carol : 12/17/1998
carol : 10/14/1998
carol : 9/29/1998
alopez : 9/17/1998
terry : 10/28/1997
mark : 10/27/1997
terry : 10/23/1997
mimadm : 1/14/1995
davew : 8/15/1994
pfoster : 4/5/1994
warfield : 3/4/1994
carol : 6/24/1992
carol : 4/1/1992

# 167250

PAGET DISEASE OF BONE 3; PDB3


DO: 0081366;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
5q35.3 Paget disease of bone 3 167250 Autosomal dominant 3 SQSTM1 601530

TEXT

A number sign (#) is used with this entry because of evidence that Paget disease of bone-3 (PDB3) is caused by heterozygous mutation in the SQSTM1 gene (601530) on chromosome 5q35.


Description

Paget disease is a metabolic bone disease characterized by focal abnormalities of increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Bone lesions in this disorder show evidence of increased osteoclastic bone resorption and disorganized bone structure. See reviews by Ralston et al. (2008) and Ralston and Albagha (2014).

Genetic Heterogeneity of Paget Disease of Bone

Also see PDB2 (602080), caused by mutation in the TNFRSF11A gene (603499) on chromosome 18q21; PDB4 (606263), mapped to chromosome 5q31; PDB5 (239000), caused by mutation in the TNFRSF11B gene (602643) on chromosome 8q24; and PDB6 (616833), caused by mutation in the ZNF687 gene (610568) on chromosome 1q21.

Suggestive linkage of a form of PDB to chromosome 6p (PDB1) was reported by Fotino et al. (1977); however, further studies did not confirm linkage to this site (Moore and Hoffman, 1988; Nance et al., 2000; Good et al., 2001).


Clinical Features

Paget disease of bone usually occurs in persons over the age of 40 years (Klein and Norman, 1995) and mainly affects the axial skeleton. Approximately 5% of patients present symptoms requiring treatment, the most frequent complaints being bone pain, enlargement, and deformities at the pagetic site (Kanis, 1998). Other manifestations of the disease include increased susceptibility to fractures, deafness, and neurologic complications (Hamdy, 1995).

In 5 patients with ancestry in southern Italy, Jacobs et al. (1979) described giant cell tumor as a complication of Paget disease of bone. Three of the patients were related. High doses of dexamethasone resulted in dramatic shrinking of tumors. Wu et al. (1991) reported 2 sisters and a brother with longstanding (35 years in 1) polyostotic Paget disease. Two of them developed osteogenic sarcoma at sites unrelated to surgical procedures, one in the sacrum and one in the calvaria. Both died shortly after diagnosis of malignancy because of aggressive spread of the tumor. The 3 sibs came from Castallamarre, Italy, which is approximately 10 km from Avellino where the ancestors of the patients of Jacobs et al. (1979) lived.


Inheritance

Reports of familial aggregation of Paget disease of bone are rather numerous, including occurrence in successive generations. McKusick (1960) reviewed 35 pedigrees reported to 1956 and added 2 others. In only 1 family, that of van Bogaert (1933), was there male-to-male transmission. In this family, all affected members and some unaffected members had retinitis pigmentosa, which may have been an independent, i.e., coincidental, genetic disorder.

Jones and Reed (1967) observed 6 cases in 3 generations of a family. Evens and Bartter (1968) described 7 definite and 2 probable cases in 1 kindred.

Leach et al. (2001) reviewed Paget disease, noting that in a study of the frequency and characteristics of the familial aggregation of PDB in Spain, Morales-Piga et al. (1995) found that 40% of their index cases had at least 1 first-degree relative affected with PDB. In the pedigrees they reported, PDB seemed to be transmitted through either parent, suggesting an autosomal dominant mode of inheritance.

Siris (1994) conducted an epidemiologic study of PDB in the United States, using questionnaires completed by 864 patients with physician-diagnosed PDB, and compared these results to 500 controls of similar age. A history of PDB was noted in a first-degree relative in 12% of the patients, compared with only 2% of controls. The risk of first-degree relatives of a PDB patient developing PDB was 7 times greater than for an individual without an affected relative. The cumulative risk for developing PDB up to age 90 for a first-degree relative of a patient was 9% compared with 2% in individuals with unaffected relatives. The authors concluded that these data are good evidence that genetics plays a role in the acquisition of the disease.


Pathogenesis

See 147620 for evidence that interleukin-6 is involved in the hyperplasia and hypertrophy of osteoclasts in Paget disease.

In addition to the genetic etiology of Paget disease, electron microscopic demonstration of virus-like bodies in bone cells of patients with Paget disease suggests a viral etiology (Mills and Singer, 1976). Winfield and Sutherland (1981) could find no serologic support for the suggestion of Rebel et al. (1976) that the inclusions represent measles virus. In all 25 biopsies showing histologic evidence of Paget disease, derived from 22 patients, electron microscopy showed characteristic nuclear and cytoplasmic inclusions in the osteoclasts (Harvey et al., 1982). Osteocytes, osteoblasts, hematopoietic cells and connective tissue cells lacked inclusions. The intranuclear inclusions consisted of stacked rows or complex whorls of tubular filaments, each of 12 to 15 mm diameter, often arranged in a paracrystalline array. The frequency of occurrence of inclusions in osteoclasts and in their individual nuclei correlated with the histologic severity of the disease process. The similarity of the inclusions to paramyxovirus inclusion bodies (particularly those of measles) supported, in the view of the authors, the hypothesis that Paget disease is a slow virus infection.

Concentration of cases in Lancashire, England (Barker et al., 1980) and in Australia (Gardner et al., 1978) suggests an important environmental factor in etiology.

Cody et al. (1997) noted similarities between Paget disease and familial expansile osteolysis (FEO; 174810). The histologic bone lesions of FEO appeared to be similar to pagetic lesions, although they occurred at a much earlier age and were more severe. Furthermore, as in Paget disease, the osteoclasts in patients with FEO contain paramyxoviral-like nuclear inclusions. Cody et al. (1997) reviewed the evidence suggesting a viral etiology of Paget disease.


Clinical Management

Singer et al. (1998) treated 13 patients with severe Paget disease of bone (mean serum alkaline phosphatase level 17 times the upper limit of normal) with 30 mg oral risedronate daily for 8 weeks. All patients who completed the study had a decrease in serum alkaline phosphatase levels of at least 77% from the baseline. Oral risedronate was well tolerated by the patients. Only 1 patient discontinued treatment because of an adverse event (diarrhea) thought to be related to risedronate therapy.

Noor and Shoback (2000) stated that therapy with bisphosphonate drugs is the treatment of choice.


Mapping

Laurin et al. (2001) performed genetic linkage analysis in 24 large French Canadian families (479 individuals) in which Paget disease was segregating as an autosomal dominant trait. After excluding linkage to the PDB2 locus (602080), they performed a genomewide scan on the 3 most informative family nuclei. Lod scores greater than 1.0 were found at 7 locations. The disorder in 8 of the families showed strong linkage to chromosome 5q35-qter, and the disease locus was designated PDB3. Under heterogeneity, a maximum lod score of 8.58 was obtained at D5S2073 at theta = 0.10. The same characteristic haplotype was carried by all patients in the 8 families, suggesting a founder effect. A recombination event in a key family confined the disease region within a 6-cM interval between D5S469 and the telomere. The disorder in the 16 other families, with very low conditional probability of linkage to 5q35-qter, showed linkage to 5q31 (PDB4; 606263).

Hocking et al. (2001) conducted a genomewide search in 319 individuals from 62 kindreds with familial PDB who were predominantly of British descent. The pattern of inheritance in the study group as a whole was consistent with autosomal dominant transmission of the disease. Parametric multipoint linkage analysis, under a model of heterogeneity, identified 3 chromosomal regions with lod scores above the thresholds for suggestive linkage. These included 5q35; maximum lod score of 3.0 at 189.63 cM between markers D5S400 and D5S408. Two-point linkage analysis with a series of markers from the 5q35 region in another large kindred with autosomal dominant familial PDB also supported linkage to the candidate region with a maximum lod score of 3.47 at D5S2034 (187.8 cM). These data indicated the presence of several susceptibility loci for PDB and identified a strong candidate locus for the disease on 5q35.


Heterogeneity

Nance et al. (2000) reported the identification and clinical characterization of a large pedigree with Paget disease in which the disorder was not linked to the 18q region, thus confirming genetic heterogeneity. The disorder in this pedigree was clinically indistinguishable from Paget disease linked to chromosome 18 and differed from sporadic Paget disease only in a lower age of onset in some affected individuals.

Associations Pending Confirmation

In a genomewide search in 319 individuals from 62 kindreds, predominantly of British descent, with familial PDB, Hocking et al. (2001) identified 3 chromosomal regions with lod scores above the threshold for suggestive linkage. These were on chromosomes 2q36 (lod score 2.7 at 218.24 cM), 5q35 (lod score 3.0 at 189.63 cM), and 10p13 (lod score 2.6 at 41.43 cM). For each of these loci, formal heterogeneity testing with HOMOG supported a model of linkage with heterogeneity, as opposed to no linkage or linkage with homogeneity.

In a large pedigree with PDB, Good et al. (2001) found significantly low lod scores for linkage at the PDB1 and PDB2 loci. In 1 branch of this family, a 'subpedigree' that showed a significantly lower age at diagnosis than the rest of the pedigree, Good et al. (2002) found linkage to 18q23 (maximum 2-point lod score of 4.23 at theta = 0.0 with marker D18S1390). Good et al. (2002) found no mutations in exon 1 of the TNFRSF11A gene in affected members of the subpedigree.

Albagha et al. (2010) performed a genomewide association study in 750 individuals with PDB without SQSTM1 mutation in 1,002 controls and identified 3 candidate disease loci that were then replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 near the CSF1 gene (120420) (p = 5.38 x 10(-24)). A significant association was also observed with rs1561570 on 10p13 within the OPTN gene (602432) (p = 6.09 x 10(-13)). Albagha et al. (2010) also confirmed linkage with PDB of a region on chromosome 18q21 near the TNFRSF11A gene, represented by rs3018362 (p = 5.27 x 10(-13)).

Albagha et al. (2011) extended their previous study of PDB and identified 3 new loci, confirming their association with PDB in 2,215 affected individuals (cases) and 4,370 controls from 7 different populations. The new associations were with rs5742915 within PML (102578) on chromosome 15q24 (odds ratio = 1.34, p = 1.6 x 10(-14)), rs10498635 within RIN3 (610223) on chromosome 14q32 (odds ratio = 1.44, p = 2.55 x 10(-11)), and rs4294134 within NUP205 (614352) on chromosome 7q33 (odds ratio = 1.45, p = 8.45 x 10(-10)). Albagha et al. (2011) stated that their data also confirmed the association with TM7SF4 (605933) on chromosome 8q22 (rs2458413, odds ratio = 1.40, p = 7.38 x 10(-17)) with PDB. These 7 loci explained approximately 13% of the familial risk of PDB.


Molecular Genetics

By screening for mutations in the SQSTM1 gene in French Canadian families with Paget disease of bone mapping to 5q35-qter, Laurin et al. (2002) identified a recurrent heterozygous nonconservative missense mutation (P392L; 601530.0001) on 2 different haplotypes defined by intragenic SNPs. The mutation occurred at a hypermutable CpG dinucleotide, suggesting that it arose by deamination of a methylated cytosine. The mutation was not present in 291 control individuals.

In affected members of 4 families with Paget disease of bone, Hocking et al. (2002) identified a heterozygous 1-bp insertion (c.1224insT; 601530.0002) in the SQSTM1 gene.

In affected members of an Australian family with Paget disease of bone, Hocking et al. (2002) identified a splice site mutation in the SQSTM1 gene (601530.0003).


History

Paget (1877) first described this localized skeletal disease as osteitis deformans.

Fotino et al. (1977) found possible linkage of PDB to the HLA region of chromosome 6p, but the lod score of 2.44 did not reach the usually accepted level of proof. Moore and Hoffman (1988) could not demonstrate linkage with MHC in a 2-generation family. Nance et al. (2000) and Good et al. (2001) found no linkage of PDB with chromosome 6p.


See Also:

Haslam et al. (1998); Montagu (1949); Sofaer et al. (1983)

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Contributors:
Carol A. Bocchini - updated : 7/1/2015
Victor A. McKusick - updated : 6/7/2000
John A. Phillips, III - updated : 9/29/1998
Victor A. McKusick - updated : 10/23/1997

Creation Date:
Victor A. McKusick : 6/2/1986

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