DO: 0081365;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18q21.33 | {Paget disease of bone 2, early-onset} | 602080 | Autosomal dominant | 3 | TNFRSF11A | 603499 |
A number sign (#) is used with this entry because of evidence that susceptibility to Paget disease of bone-2 (PDB2) is conferred by heterozygous mutation in the TNFRSF11A gene (603499), which encodes RANK, on chromosome 18q21.
Heterozygous mutation in the TNFRSF11A gene can also cause familial expansile osteolysis (FEO; 174810), which shows some overlapping features.
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).
For a discussion of genetic heterogeneity of Paget disease of bone, see 167250.
Nakatsuka et al. (2003) reported the clinical features of a 3-generation Japanese family with PDB2 originally reported by Hughes et al. (2000). There were 6 affected individuals, 1 of whom was deceased. The patients presented with skeletal symptoms during their teens and early twenties. Features included pain and bony deformities of the lower limbs, such as bowing, bony enlargement of the proximal and distal interphalangeal joints of the hands, swelling and deformity of the jaw associated with loosening and loss of teeth, and progressive hearing loss. Bone scans showed increased tracer uptake in multiple regions, including the upper and lower limbs, pelvis, vertex of the skull, mandible, and maxilla. Radiographs in more severely affected patients showed expansion and deformity of the affected bones with mixed lytic and sclerotic lesions. Bone biopsy of 1 patient showed increased bone turnover with prominent osteoclast activity and disorganized collagen fibrils. Laboratory studies showed increased alkaline phosphatase.
Whyte et al. (2014) reported a 13-year-old Brazilian girl with a severe form of early-onset PDB2. Prenatal ultrasound showed a short and bowed right femur. She presented at age 3 years with dentoosseous disease, including shedding of the teeth, early resorption of primary tooth roots, and hypoplasia of permanent teeth. She had early-onset deafness associated with missing ossicles and eroded cochleas. Laboratory studies showed markers of increased bone turnover, and radiographs showed thickening in regions of the skull, tubular bone widening, cortical thickening, coarse trabeculation, and osteosclerosis. Osteolytic lesions were not observed. Bone histology showed accelerated remodeling with abundant osteoclasts. The patient developed transient but symptomatic hypercalcemia associated with immobilization. She was diagnosed with juvenile Paget disease; treatment with pamidronate resulted in significant improvement.
The transmission pattern of PBD2 in the family reported by Nakatsuka et al. (2003) was consistent with autosomal dominant inheritance.
Because of clinical similarities of Paget disease of bone to familial expansile osteolysis, which had been mapped to 18q21-q22, Van Hul et al. (1997) performed linkage analysis in 8 large 'pagetic' families from varied ethnic backgrounds, using a panel of polymorphic microsatellite markers spanning the region of interest on 18q. In all families, the transmission pattern was consistent with autosomal dominant inheritance with high penetrance by the age of 65. In their full report of these studies, Haslam et al. (1998) stated that summated 2-point lod scores were suggestive for linkage with several markers, with a maximum lod score of 2.95 for D18S60 at theta = 0.0. HOMOG analysis suggested genetic heterogeneity, with evidence for linkage in 5 families and against linkage in 3 families. Multipoint linkage analysis in the 5 linked families showed a maximum lod score of 3.89 at marker D18S465. Linkage was excluded in 1 family.
By study of a large kindred with a high incidence of Paget disease, Cody et al. (1997) determined that Paget disease was linked to genetic markers in the same region of chromosome 18 as that for FEO. Their analysis yielded a 2-point lod score of 3.40 with the genetic marker D18S42, a marker tightly linked to the FEO locus.
In 4 families with Paget disease of bone and possible linkage to 18q, Hughes et al. (2000) performed mutation screening and in one of them found a duplication involving bases 75-101 in exon 1 of the TNFRSF11A gene (603499.0002) that cosegregated with the disease. No TNFRSF11A mutations were found in the other 3 PDB families, or in cDNA prepared from affected bone of 5 patients with sporadic PDB.
In a 13-year-old Bolivian girl with PDB2, Whyte et al. (2014) identified a heterozygous 15-bp duplication (g.87dup15; 603499.0009) in exon 1 of the TNFRSF11A gene, resulting in an in-frame insertion of 5 amino acids in the signal peptide. The authors stated that the mutation resulted in the same pentapeptide expansion that was caused by a g.84dup15 mutation in the TNFRSF11A gene that was found in a mother and daughter with a variant form of FEO called expansile skeletal hyperphosphatasia by Whyte and Hughes (2002).
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] [Full Text: https://doi.org/10.1086/301601]
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] [Full Text: https://doi.org/10.1359/jbmr.1998.13.6.911]
Hughes, A. E., Ralston, S. H., Marken, J., Bell, C., MacPherson, H., Wallace, R. G. H., van Hul, W., Whyte, M. P., Nakatsuka, K., Hovy, L., Anderson, D. M. Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nature Genet. 24: 45-48, 2000. [PubMed: 10615125] [Full Text: https://doi.org/10.1038/71667]
Nakatsuka, K., Nishizawa, Y., Ralston, S. H. 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. [PubMed: 12929927] [Full Text: https://doi.org/10.1359/jbmr.2003.18.8.1381]
Ralston, S. H., Albagha, O. M. E. Genetics of Paget's disease of bone. Curr. Osteoporos. Rep. 12: 263-271, 2014. [PubMed: 24988994] [Full Text: https://doi.org/10.1007/s11914-014-0219-y]
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] [Full Text: https://doi.org/10.1016/S0140-6736(08)61035-1]
Van Hul, W., Haslam, S. I, Morales Piga, A., Balemans, W., Haites, N. E., San Millan, J. L., Navio, T., Nakatsuka, K., Willems, P. J., Ralston, S. H. Suggestion for a susceptibility locus for Paget's disease of bone on chromosome 18 and for genetic heterogeneity. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A298 only, 1997.
Whyte, M. P., Hughes, A. E. Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis. J. Bone Miner. Res. 17: 26-29, 2002. [PubMed: 11771666] [Full Text: https://doi.org/10.1359/jbmr.2002.17.1.26]
Whyte, M. P., Tau, C., McAlister, W. H., Zhang, X., Novack, D. V., Preliasco, V., Santini-Araujo, E., Mumm, S. Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK. Bone 68: 153-161, 2014. [PubMed: 25063546] [Full Text: https://doi.org/10.1016/j.bone.2014.07.019]