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Clinical and genetic analysis in a Chinese family with familial tumoral calcinosis
S34
ABSTRACTS / Bone 43 (2008) S26–S37
OR22 The injury-induced initial inflammatory response modulates downstream bony repair events in the injured growth plate cartilage Cory Xian 1, Fiona Zhou 2, Rosa Chung 2, Michaela Scherer 3, Bruce Foster 3 1 University of South Australia, Adelaide, Australia 2 University of Adelaide, Australia 3 Women's and Children's Hospital, Adelaide, Australia Growth plate trauma injuries are often repaired by bony tissue which results in bone bridge formation and bone growth defects in children. How this bony repair occurs remains unclear. Using a tibial growth plate injury model in young rats, this study characterised the injury responses and bony repair mechanisms. It is observed that bony tissue formation at injured growth plate occurs within 2 weeks and is preceded sequentially by inflammatory, fibrogenic, chondrogenic and osteogenic, and remodelling responses. The initial inflammatory response was rapid and acute at the injured growth plate, with neutrophil-dominant inflammatory infiltration and upregulation of inflammatory molecules (including CINC-1, p38 MAP kinase, Cox-2, iNOS, TNF-α, and IL-1) peaking on day 1 and subsiding on day 3. After the inflammatory response, the infiltrated fibrous mesenchymal cells undergo chondrogenic and osteogenic events, resulting in both endochondral and intramembrous bone formation and bony repair. Experiments inhibiting the initial inflammatory response with some specific inhibitors or neutralising antibody in rats with growth plate injury showed that the inflammatory event is important in regulating downstream events as it recruits inflammatory cells and produces important molecules such as growth factors PDGF-B, FGF-2, TGF-β1, and BMPs that regulate subsequent repair events and influence the proportions of mesenchymal, cartilaginous or bony repair tissues. In conclusion, bone bridge formation at the injured growth plate is preceded sequentially by inflammatory, fibrogenic, chondrogenic and osteogenic responses, and occurs through intramembranous and endochondral ossification mechanisms, and the initial inflammatory response is important in influencing downstream bony healing events. doi:10.1016/j.bone.2008.07.042
OR23 Genome-wide association study of BMD and hip geometry indices. The Framingham Osteoporosis Study Yi-Hsiang Hsu 1, Serkalem Demissie-Banjaw 2, Yanhua Zhou 2, Estelle Bianchi 3, Serge Ferrari 3, L. Adrienne Cupples 2, David Karasik 1, Douglas Kiel 1 1 Hebrew SeniorLife and Harvard Medical School, Boston, MA, USA 2 Biostat., BU, School of Public Health, Boston, MA, USA 3 Division of Bone Diseases, Geneva University Hospital, Geneva, Switzerland Despite significant progress in understanding the genetic basis for osteoporosis, efforts to identify genes associated with BMD and bone geometry traits have been incomplete. With the completion of the HapMap project, GWA became a promising tool to dissect complex diseases. We have undertaken a GWA study using the Affymetrix 550K SNP chips to localize susceptibility genes for BMD at the lumbar spine and femoral neck and geometric indices of the hip (femoral neck-shaft angle, femoral neck length and narrow-neck width) in the Framingham Osteoporosis Study. 433,510 SNPs passed quality control criteria (call rate ≥ 95%, HWE p ≥ 10− 6 and MAF ≥ 0.01) in 2073 women and 1554 men (mean age 62.5 yrs) from 677 extended pedigrees. We conducted population- and family-based analyses, using sex-specific
residual trait values adjusted for age, height, BMI, and estrogen/ menopause (women). For population-based analyses, we used linearmixed effects (LME) models that account for individual correlations within families. A principle component analysis (EIGENSTRAT) for all SNPs was performed to explicitly model differences of individuals' ancestral genetic background. The first 4 principle components (PCs) were significantly associated with bone traits; therefore, to minimize spurious associations from population substructure, we adjusted for PCs in LME models. After adjustment, the λGC were ≤1.02. Familybased association test (FBAT) weighted by rank order of LME statistics was used to estimate the genome-wide significance. To test whether associated genes were expressed in bone, we measured mRNA of PTHdifferentiated primary osteoblasts and further examined an embryonic mouse gene expression database for in situ localization in skeletal tissue. Several associations with bone traits achieved genome-wide significance level (p b 10− 8), i.e. SNPs on BMP10, PTPRD, MYC, SLC16A4, IL6 and PRKG1 genes. All except for BMP10 and MYC were expressed in osteoblasts. In addition, a gene-set enrichment analysis by Gene Ontology annotation for the genes selected from the most significant SNPs suggested significant clustering of genes involved in central nervous system (CNS) development. The 100 most significant SNPs from each trait are being further evaluated in N2650 men and 5850 women from 2 independent studies (Rotterdam and the UK Twins Studies). In conclusion, our results reveal novel candidate genes and pathways to further elucidate the etiology of osteoporosis through the determination of BMD and bone geometry. Our findings further suggest an interaction between the CNS and skeleton. doi:10.1016/j.bone.2008.07.256
OR24 Clinical and genetic analysis in a Chinese family with familial tumoral calcinosis Lihao Sun 1, Xiaoyi Ding 2, Lin Zhao 1, Jianmin Liu 1, Guang Ning 1 1 Department of Endocrinology and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao-Tong University Medical School, Shanghai, China 2 Department of Radiology, Rui-jin Hospital, Shanghai Jiao-Tong University Medical School, Shanghai, China Objective: To analyze the clinical manifestations of one Chinese FTC pedigree and to identify mutations in GALNT3 or FGF23 gene. Methods: Clinical features and laboratory data were collected from a 13 year old boy who was suspected to suffer from FTC. A hip mass resection was performed on him, with pathohistological examination to confirm the diagnosis. Complete family history was obtained and his family members (9 in total) donated their blood for DNA analysis. All of the exons of the GALNT3 and FGF23 gene were amplified by the polymerase chain reaction (PCR), and direct sequence determination was applied to the amplified fragments. Results: The proband was diagnosed as FTC according to the clinical manifestations and laboratory findings, including a growing hip mass in the d isease course, hype rphosphatemia, normocalcemia, metastatic calcifications around the right hip and pathohistological examination confirming the diagnosis of tumoral calcinosis. His elder sister also had similar metastatic calcifications. Mutation detection revealed compound homozygosity for two novel mutations of GALNT3 in exon2 (R180H and I220N) in the proband and his sister. Their parents don't present any clinical characteristics of FTC, but both have heterozygote mutations of GALNT3 in exon2, R180H and I220N. The clinical features and the identified nucleotide changes were not found in the other members in the whole family. The mutation of FGF23 was not found in the proband and other members of the whole family.
ABSTRACTS / Bone 43 (2008) S26–S37
Conclusion: In this family with FTC, two novel mutations in exon2 of GALNT3 gene were found. It is also the first study to report the identification of GALNT3 gene mutation in Chinese subjects. doi:10.1016/j.bone.2008.07.044
OR25 Is decreased BMD associated with less severe lumbar disc degeneration? Yixiang Wang 1, James F. Griffith 1, Heather Ting Ma 2, Anthony W.L. Kwok 2, Ping Chung Leung 2, Jason Leung 2, David K.W. Yeung 1 1 Department of Diagnostic Radiology and Organ Imaging, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China 2 Jockey Club Centre for Osteoporosis Care and Control, Public Health School, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China Objective: Aiming at a better understanding if reduced bone mineral density (BMD) in vertebrae aggravates or protects against disc degeneration, we studied the relationship between BMD and lumbar disc degeneration using a recently described discriminatory MR grading system in a large number of healthy elderly subjects. Methods: 359 healthy asymptomatic elderly subjects (137 males, 222 females, age = 73.3 ± 4.3 years) were recruited from local community centers for clinical assessment, BMD measurement by DXA and sagittal T2-weighted MRI of the lumbar spine using a 1.5 T magnet. Subjects were divided into three groups, i.e. normal BMD, osteopenia, and osteoporosis, according to T-score and WHO criteria, where 141 (39%) had normal BMD, 107 (30%) had osteopenia, and 111 (31%) had osteoporosis. Disc degeneration was graded on the midsagittal image using a specially designed 8-level grading system. Results: After removing the effect of age, MR disc degeneration severity grade was 5.2% ∼ 11.0% lower at L4/L5 (p = 0.007), L3/L4 (p b 0.001) and L2/L3 (p = 0.003) in osteopenic or osteoporotic subjects compared to that of normal subjects. Conversely, there was a 2.6% ∼ 6% increase in MR disc degeneration severity grade at L1/L2 (p = 0.01) in osteopenic or osteoporotic subjects compared to normal subjects. No significant difference was found in the MR disc degeneration grade at L5/S1. Overall mean disc degeneration grade of all five levels (L1/L2 to L5/S1) was significantly smaller (p = 0.001) in subjects with reduced BMD than those with normal BMD. Conclusion: This study shows that reduced BMD in vertebrae is associated with less severe lumbar disc degeneration. Microarchitectural deterioration associated with reduced BMD leads to endplate weakening and loss of vertebral body height, a process that allows the disc to push into the endplates and expand. This possibly facilitates dissipation of forces applied to the disc and thus helps reduce disc damage. doi:10.1016/j.bone.2008.07.045
OR26 Association of CYP1A1 gene polymorphisms with sex hormone and bone mineral density in old aged male Jing Sun, Xiaofen Pang Department of Geraeology in Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Objective: To investigate the association of CYP1A1 gene polymorphisms in exon7 with sex hormone level and bone mineral density (BMD) in aged males, which is a hormone-dependent health issue.
S35
Methods: One hundred and ninety-eight males aged above 60 in Shanghai (mean age, 77.16 ±6.27 years) participated in the study. BMD at lumbar spines 2–4 and the left proximal femur (total tip, ward's, femoral neck and trochanter) were measured by dual-energy X-ray absorptiometry. A4889G and C4887A genotypes in exon7 were analyzed by polymerase chain reaction and gene sequencing, serum sex hormone (free testosterone, testosterone and estradiol) by ultrasensitive radioimmunoassay, serum sex hormone-binding globulin by immunoradiometric assay. Differences in the level of sex hormone and BMD among the different variants were analyzed by one-way ANOVA. Results: We found that subjects carrying the GG genotype for the A4889G polymorphism of the CYP1A1 gene have significantly lower BMD (g/cm2) at lumbar spine 2–4, ward's and total tip than GA/AA subjects (pb 0.05). But the BMD of femoral neck and trochanter among three genotypes or BMD in all regions between A/G allele groups were not statistical different. Meanwhile, no significant effect of this gene polymorphism was detected on serum sex hormone level. After adjusting for BMI, BMD of the group carrying G allele had significantly lower BMD (g/cm2) in all regions of the femur than the group with the A allele. Genotype frequencies for this polymorphism showed AA as the most common genotype (107/198), followed by GA (80/198), whereas AA was rare (11/198). The C4887A polymorphism cannot be detected in Shanghai males. Conclusion: Males with the G allele seem to have lower BMD, but it cannot be explained by serum sex hormone level. Our data, therefore, suggest that, the A4889G polymorphism of the CYP1A1 gene may represent a possible genetic risk factor for osteoporosis. doi:10.1016/j.bone.2008.07.046
OR27 Identification of a novel mutation (78dup27) of the TNFRSF11A gene in a Chinese family with early onset Paget's disease of bone Zhenlin Zhang The Department of Osteoporosis, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, China Objective: Paget's disease of bone (PDB) is rare in China. Previous study showed that affected individuals of early onset PDB from Japanese descent carried a 27-bp duplication at position 75 (75dup27) in TNFRSF11A gene. In here, we reported that a novel mutation 78dup27 in exon 1 of TNFRSF11A gene was identified in a Chinese family with early onset PDB. Methods: Proposita of an unconsanguineous family and 3 affected familial individuals were admitted to our hospital because of deformity affecting the lower limbs, and vertebral spine with pain. Early onset PDB was diagnosed based on the clinical presentations with the characteristics of osteolysis and osteosclerosis with bone enlargement and deformity at the affected locations on X-ray, and elevated serum alkaline phosphatase levels. Genomic DNA was extracted from 4 affected individuals and 6 phenotype normal members in a Chinese family with early onset PDB. The entire coding region of the TNFSF11A and SQSTM1 was amplified and sequenced directly. Results: We did not find SQSTM1 gene mutations in proposita and her familial members. A novel 27-bp duplication in exon 1 (78dup27) in TNFSF11A was found in four affected individuals and one phenotype normal individual. Although the same 27-bp duplication, our mutation presented at bases 78–104, and on the protein level, this 78dup27 mutation resulted in nine amino acid insertions in the RANK signal peptide. However, the duplication of nine amino acids was LLLLCALLA in our patients, rather than ALLLLCALL in affected individuals of Japanese family. The mutation was not detected in genomic DNA of 100 unrelated controls and the other five patients with sporadic PDB. Conclusions: The clinical findings in affected members of our family were similar to those bone presentations of previously reported
ABSTRACTS / Bone 43 (2008) S26–S37
OR22 The injury-induced initial inflammatory response modulates downstream bony repair events in the injured growth plate cartilage Cory Xian 1, Fiona Zhou 2, Rosa Chung 2, Michaela Scherer 3, Bruce Foster 3 1 University of South Australia, Adelaide, Australia 2 University of Adelaide, Australia 3 Women's and Children's Hospital, Adelaide, Australia Growth plate trauma injuries are often repaired by bony tissue which results in bone bridge formation and bone growth defects in children. How this bony repair occurs remains unclear. Using a tibial growth plate injury model in young rats, this study characterised the injury responses and bony repair mechanisms. It is observed that bony tissue formation at injured growth plate occurs within 2 weeks and is preceded sequentially by inflammatory, fibrogenic, chondrogenic and osteogenic, and remodelling responses. The initial inflammatory response was rapid and acute at the injured growth plate, with neutrophil-dominant inflammatory infiltration and upregulation of inflammatory molecules (including CINC-1, p38 MAP kinase, Cox-2, iNOS, TNF-α, and IL-1) peaking on day 1 and subsiding on day 3. After the inflammatory response, the infiltrated fibrous mesenchymal cells undergo chondrogenic and osteogenic events, resulting in both endochondral and intramembrous bone formation and bony repair. Experiments inhibiting the initial inflammatory response with some specific inhibitors or neutralising antibody in rats with growth plate injury showed that the inflammatory event is important in regulating downstream events as it recruits inflammatory cells and produces important molecules such as growth factors PDGF-B, FGF-2, TGF-β1, and BMPs that regulate subsequent repair events and influence the proportions of mesenchymal, cartilaginous or bony repair tissues. In conclusion, bone bridge formation at the injured growth plate is preceded sequentially by inflammatory, fibrogenic, chondrogenic and osteogenic responses, and occurs through intramembranous and endochondral ossification mechanisms, and the initial inflammatory response is important in influencing downstream bony healing events. doi:10.1016/j.bone.2008.07.042
OR23 Genome-wide association study of BMD and hip geometry indices. The Framingham Osteoporosis Study Yi-Hsiang Hsu 1, Serkalem Demissie-Banjaw 2, Yanhua Zhou 2, Estelle Bianchi 3, Serge Ferrari 3, L. Adrienne Cupples 2, David Karasik 1, Douglas Kiel 1 1 Hebrew SeniorLife and Harvard Medical School, Boston, MA, USA 2 Biostat., BU, School of Public Health, Boston, MA, USA 3 Division of Bone Diseases, Geneva University Hospital, Geneva, Switzerland Despite significant progress in understanding the genetic basis for osteoporosis, efforts to identify genes associated with BMD and bone geometry traits have been incomplete. With the completion of the HapMap project, GWA became a promising tool to dissect complex diseases. We have undertaken a GWA study using the Affymetrix 550K SNP chips to localize susceptibility genes for BMD at the lumbar spine and femoral neck and geometric indices of the hip (femoral neck-shaft angle, femoral neck length and narrow-neck width) in the Framingham Osteoporosis Study. 433,510 SNPs passed quality control criteria (call rate ≥ 95%, HWE p ≥ 10− 6 and MAF ≥ 0.01) in 2073 women and 1554 men (mean age 62.5 yrs) from 677 extended pedigrees. We conducted population- and family-based analyses, using sex-specific
residual trait values adjusted for age, height, BMI, and estrogen/ menopause (women). For population-based analyses, we used linearmixed effects (LME) models that account for individual correlations within families. A principle component analysis (EIGENSTRAT) for all SNPs was performed to explicitly model differences of individuals' ancestral genetic background. The first 4 principle components (PCs) were significantly associated with bone traits; therefore, to minimize spurious associations from population substructure, we adjusted for PCs in LME models. After adjustment, the λGC were ≤1.02. Familybased association test (FBAT) weighted by rank order of LME statistics was used to estimate the genome-wide significance. To test whether associated genes were expressed in bone, we measured mRNA of PTHdifferentiated primary osteoblasts and further examined an embryonic mouse gene expression database for in situ localization in skeletal tissue. Several associations with bone traits achieved genome-wide significance level (p b 10− 8), i.e. SNPs on BMP10, PTPRD, MYC, SLC16A4, IL6 and PRKG1 genes. All except for BMP10 and MYC were expressed in osteoblasts. In addition, a gene-set enrichment analysis by Gene Ontology annotation for the genes selected from the most significant SNPs suggested significant clustering of genes involved in central nervous system (CNS) development. The 100 most significant SNPs from each trait are being further evaluated in N2650 men and 5850 women from 2 independent studies (Rotterdam and the UK Twins Studies). In conclusion, our results reveal novel candidate genes and pathways to further elucidate the etiology of osteoporosis through the determination of BMD and bone geometry. Our findings further suggest an interaction between the CNS and skeleton. doi:10.1016/j.bone.2008.07.256
OR24 Clinical and genetic analysis in a Chinese family with familial tumoral calcinosis Lihao Sun 1, Xiaoyi Ding 2, Lin Zhao 1, Jianmin Liu 1, Guang Ning 1 1 Department of Endocrinology and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao-Tong University Medical School, Shanghai, China 2 Department of Radiology, Rui-jin Hospital, Shanghai Jiao-Tong University Medical School, Shanghai, China Objective: To analyze the clinical manifestations of one Chinese FTC pedigree and to identify mutations in GALNT3 or FGF23 gene. Methods: Clinical features and laboratory data were collected from a 13 year old boy who was suspected to suffer from FTC. A hip mass resection was performed on him, with pathohistological examination to confirm the diagnosis. Complete family history was obtained and his family members (9 in total) donated their blood for DNA analysis. All of the exons of the GALNT3 and FGF23 gene were amplified by the polymerase chain reaction (PCR), and direct sequence determination was applied to the amplified fragments. Results: The proband was diagnosed as FTC according to the clinical manifestations and laboratory findings, including a growing hip mass in the d isease course, hype rphosphatemia, normocalcemia, metastatic calcifications around the right hip and pathohistological examination confirming the diagnosis of tumoral calcinosis. His elder sister also had similar metastatic calcifications. Mutation detection revealed compound homozygosity for two novel mutations of GALNT3 in exon2 (R180H and I220N) in the proband and his sister. Their parents don't present any clinical characteristics of FTC, but both have heterozygote mutations of GALNT3 in exon2, R180H and I220N. The clinical features and the identified nucleotide changes were not found in the other members in the whole family. The mutation of FGF23 was not found in the proband and other members of the whole family.
ABSTRACTS / Bone 43 (2008) S26–S37
Conclusion: In this family with FTC, two novel mutations in exon2 of GALNT3 gene were found. It is also the first study to report the identification of GALNT3 gene mutation in Chinese subjects. doi:10.1016/j.bone.2008.07.044
OR25 Is decreased BMD associated with less severe lumbar disc degeneration? Yixiang Wang 1, James F. Griffith 1, Heather Ting Ma 2, Anthony W.L. Kwok 2, Ping Chung Leung 2, Jason Leung 2, David K.W. Yeung 1 1 Department of Diagnostic Radiology and Organ Imaging, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China 2 Jockey Club Centre for Osteoporosis Care and Control, Public Health School, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China Objective: Aiming at a better understanding if reduced bone mineral density (BMD) in vertebrae aggravates or protects against disc degeneration, we studied the relationship between BMD and lumbar disc degeneration using a recently described discriminatory MR grading system in a large number of healthy elderly subjects. Methods: 359 healthy asymptomatic elderly subjects (137 males, 222 females, age = 73.3 ± 4.3 years) were recruited from local community centers for clinical assessment, BMD measurement by DXA and sagittal T2-weighted MRI of the lumbar spine using a 1.5 T magnet. Subjects were divided into three groups, i.e. normal BMD, osteopenia, and osteoporosis, according to T-score and WHO criteria, where 141 (39%) had normal BMD, 107 (30%) had osteopenia, and 111 (31%) had osteoporosis. Disc degeneration was graded on the midsagittal image using a specially designed 8-level grading system. Results: After removing the effect of age, MR disc degeneration severity grade was 5.2% ∼ 11.0% lower at L4/L5 (p = 0.007), L3/L4 (p b 0.001) and L2/L3 (p = 0.003) in osteopenic or osteoporotic subjects compared to that of normal subjects. Conversely, there was a 2.6% ∼ 6% increase in MR disc degeneration severity grade at L1/L2 (p = 0.01) in osteopenic or osteoporotic subjects compared to normal subjects. No significant difference was found in the MR disc degeneration grade at L5/S1. Overall mean disc degeneration grade of all five levels (L1/L2 to L5/S1) was significantly smaller (p = 0.001) in subjects with reduced BMD than those with normal BMD. Conclusion: This study shows that reduced BMD in vertebrae is associated with less severe lumbar disc degeneration. Microarchitectural deterioration associated with reduced BMD leads to endplate weakening and loss of vertebral body height, a process that allows the disc to push into the endplates and expand. This possibly facilitates dissipation of forces applied to the disc and thus helps reduce disc damage. doi:10.1016/j.bone.2008.07.045
OR26 Association of CYP1A1 gene polymorphisms with sex hormone and bone mineral density in old aged male Jing Sun, Xiaofen Pang Department of Geraeology in Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Objective: To investigate the association of CYP1A1 gene polymorphisms in exon7 with sex hormone level and bone mineral density (BMD) in aged males, which is a hormone-dependent health issue.
S35
Methods: One hundred and ninety-eight males aged above 60 in Shanghai (mean age, 77.16 ±6.27 years) participated in the study. BMD at lumbar spines 2–4 and the left proximal femur (total tip, ward's, femoral neck and trochanter) were measured by dual-energy X-ray absorptiometry. A4889G and C4887A genotypes in exon7 were analyzed by polymerase chain reaction and gene sequencing, serum sex hormone (free testosterone, testosterone and estradiol) by ultrasensitive radioimmunoassay, serum sex hormone-binding globulin by immunoradiometric assay. Differences in the level of sex hormone and BMD among the different variants were analyzed by one-way ANOVA. Results: We found that subjects carrying the GG genotype for the A4889G polymorphism of the CYP1A1 gene have significantly lower BMD (g/cm2) at lumbar spine 2–4, ward's and total tip than GA/AA subjects (pb 0.05). But the BMD of femoral neck and trochanter among three genotypes or BMD in all regions between A/G allele groups were not statistical different. Meanwhile, no significant effect of this gene polymorphism was detected on serum sex hormone level. After adjusting for BMI, BMD of the group carrying G allele had significantly lower BMD (g/cm2) in all regions of the femur than the group with the A allele. Genotype frequencies for this polymorphism showed AA as the most common genotype (107/198), followed by GA (80/198), whereas AA was rare (11/198). The C4887A polymorphism cannot be detected in Shanghai males. Conclusion: Males with the G allele seem to have lower BMD, but it cannot be explained by serum sex hormone level. Our data, therefore, suggest that, the A4889G polymorphism of the CYP1A1 gene may represent a possible genetic risk factor for osteoporosis. doi:10.1016/j.bone.2008.07.046
OR27 Identification of a novel mutation (78dup27) of the TNFRSF11A gene in a Chinese family with early onset Paget's disease of bone Zhenlin Zhang The Department of Osteoporosis, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, China Objective: Paget's disease of bone (PDB) is rare in China. Previous study showed that affected individuals of early onset PDB from Japanese descent carried a 27-bp duplication at position 75 (75dup27) in TNFRSF11A gene. In here, we reported that a novel mutation 78dup27 in exon 1 of TNFRSF11A gene was identified in a Chinese family with early onset PDB. Methods: Proposita of an unconsanguineous family and 3 affected familial individuals were admitted to our hospital because of deformity affecting the lower limbs, and vertebral spine with pain. Early onset PDB was diagnosed based on the clinical presentations with the characteristics of osteolysis and osteosclerosis with bone enlargement and deformity at the affected locations on X-ray, and elevated serum alkaline phosphatase levels. Genomic DNA was extracted from 4 affected individuals and 6 phenotype normal members in a Chinese family with early onset PDB. The entire coding region of the TNFSF11A and SQSTM1 was amplified and sequenced directly. Results: We did not find SQSTM1 gene mutations in proposita and her familial members. A novel 27-bp duplication in exon 1 (78dup27) in TNFSF11A was found in four affected individuals and one phenotype normal individual. Although the same 27-bp duplication, our mutation presented at bases 78–104, and on the protein level, this 78dup27 mutation resulted in nine amino acid insertions in the RANK signal peptide. However, the duplication of nine amino acids was LLLLCALLA in our patients, rather than ALLLLCALL in affected individuals of Japanese family. The mutation was not detected in genomic DNA of 100 unrelated controls and the other five patients with sporadic PDB. Conclusions: The clinical findings in affected members of our family were similar to those bone presentations of previously reported