更新于：2024-11-01

Familial Paget's Disease of Bone

家族性佩吉特氏病

更新于：2024-11-01

基本信息

别名

Familial Paget's disease of bone、Paget disease of bone, type 1、家族性佩吉特氏骨病

简介-

关联

项与家族性佩吉特氏病相关的药物

Elcatonin

依降钙素

靶点

CALCR

作用机制

CALCR抑制剂

在研机构

Asahi Kasei Corp. [+1]

原研机构

Asahi Kasei Corp.

在研适应症

家族性佩吉特氏病 [+2]

非在研适应症

偏瘫 [+1]

最高研发阶段批准上市

首次获批国家/地区

日本

首次获批日期1982-06-15

项与家族性佩吉特氏病相关的临床试验

ACTRN12605000294651 / CompletedN/AIIT

Prevalence and skeletal extent on bone scintigraphy of Paget's disease in people inheriting mutations in the Sequestosome1 (SQSTM1) gene

开始日期2004-05-21

申办/合作机构-

100 项与家族性佩吉特氏病相关的临床结果

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100 项与家族性佩吉特氏病相关的转化医学

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0 项与家族性佩吉特氏病相关的专利（医药）

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项与家族性佩吉特氏病相关的文献（医药）

2023-05-01·Bone

Early identification of a 12-bp tandem duplication in TNFRSF11A encoding receptor activator of nuclear factor-kappa B (RANK): Clinical characterization and response to bisphosphonate therapy

Article

作者: Vajravelu, Mary Ellen ; Shekdar, Karuna V ; Levine, Michael A ; Craven, Meghan ; Whyte, Michael P ; Mumm, Steven ; Mancilla, Edna E

INTRODUCTIONUltra-rare mendelian osteolytic disorders caused by different length in-frame activating duplications within exon 1 of TNFRSF11A encoding receptor activator of nuclear factor-kappa B (RANK) comprise familial expansile osteolysis (FEO), expansile skeletal hyperphosphatasia (ESH), early-onset familial Paget's disease of bone (PDB2), juvenile Paget's disease 2 (JPD2), and panostotic expansile bone disease (PEBD). FEO typically presents with childhood-onset deafness followed by resorption of permanent dentition, and then appendicular bone pain, fractures, and deformities from progressive focal expansile osteolytic lesions emerging from a background of generalized high bone turnover. An 18-bp duplication in TNFRSF11A has been reported in all kindreds with FEO, whereas a 12-bp duplication was found in the young man with PEBD complicated by a massive jaw tumor. We report the clinical course and successful treatment with bisphosphonates of a girl with the 12-bp duplication yet a skeletal phenotype seemingly milder than PEBD.CASE PRESENTATION AND DISCUSSIONThis 10-year-old girl presented for dental and orthodontic treatment and was found to have progressive external tooth root resorption. Speech delay was identified at age 18 months, and audiological evaluation showed both conductive and sensorineural hearing loss subsequently treated with a cochlear implant at age 3 years. Biochemical studies indicated increased bone turnover with elevated urinary N-telopeptide levels and serum alkaline phosphatase in the upper normal range. Low lumbar spine bone mineral density (BMD) was revealed by dual-energy X-ray absorptiometry, but whole-body Technetium-99 m bone scintigraphy was normal. Genetic testing identified the identical de novo 12-bp duplication within exon 1 of TNFRSF11A harbored by the young man with PEBD and massive jaw tumor. Bisphosphonate treatment, initiated with one dose of intravenous zoledronic acid that caused prolonged hypocalcemia, then comprised weekly oral alendronate that decreased bone turnover markers and normalized her BMD.CONCLUSIONConstitutive activation of RANK signaling should be considered a possible cause in any young person with rapid bone turnover, particularly in the context of early-onset deafness and/or root resorption of permanent teeth. Early diagnosis and anti-resorptive treatment, given judiciously to avoid sudden and prolonged hypocalcemia, may prevent further skeletal disease.

2020-12-01·Journal of Bone and Mineral Research1区 · 医学

Insertion Mutation in Tnfrsf11a Causes a Paget's Disease–Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice

1区 · 医学

Article

作者: Rose, Lorraine ; Albagha, Omar M.E. ; Ralston, Stuart H. ; van't Hof, Rob J. ; Alonso, Nerea ; Wani, Sachin

ABSTRACTEarly onset familial Paget's disease of bone (EoPDB), familial expansile osteolysis, and expansile skeletal hyperphosphatasia are related disorders caused by insertion mutations in exon 1 of the TNFRSF11A gene, which encodes receptor activator of nuclear factor κB (RANK) protein. To understand the mechanisms underlying these disorders, we developed a mouse model carrying the 75dup27 mutation which causes EoPDB. Mice heterozygous for the mutation (Tnfrsf11a75dup27/−) developed a PDB-like disorder with focal osteolytic lesions in the hind limbs with increasing age. Treatment of these mice with zoledronic acid completely prevented the development of lesions. Studies in vitro showed that RANK ligand (RANKL)-induced osteoclast formation and signaling was impaired in bone marrow cells from Tnfrsf11a75dup27/− animals, but that osteoclast survival was increased independent of RANKL stimulation. Surprisingly, Tnfrsf11a75dup27/75dup27 homozygotes had osteopetrosis at birth, with complete absence of osteoclasts. Bone marrow cells from these mice failed to form osteoclasts in response to RANKL and macrophage colony-stimulating factor (M-CSF) stimulation. This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling. In homozygous form, however, the mutation causes osteopetrosis due to failure of osteoclast formation and insensitivity to RANKL stimulation. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..

2019-06-01·Bone Reports

Targeted sequencing of DCSTAMP in familial Paget's disease of bone

Article

作者: Walsh, J P ; Rea, S L ; Pavlos, N J ; Sultana, M A ; Ward, Lynley

Paget's disease of bone (PDB) has a strong genetic component. Variants in SQSTM1 are found in up to 40% of patients with a family history of the disease, where a pattern of autosomal dominance with incomplete penetrance is apparent. By contrast, SQSTM1 variants are only found in up to 10% of patients with sporadic disease. It has been hypothesised that the remaining genetic susceptibility to PDB, particularly in familial cases, could be explained by rare genetic variants in loci previously identified by Genome Wide Association Studies. It is likely that polygenic factors are involved in many individuals. In this study we utilised whole exome sequencing to investigate predisposing genetic factors in an unsolved PDB kindred and identified a c.1189C > T p.L397F variant in DC-STAMP, also known as TM7SF4, that co-segregated with disease. DCSTAMP was identified as a gene of interest in PDB following Genome Wide Association Studies and has been previously shown to play critical roles in osteoclast fusion. The variant we identified has also been reported in association with PDB in a French-Canadian cohort however the significance of this variant was inconclusive. Targeted screening of DCSTAMP in our familial cohort of PDB patients revealed an additional 8 variants; however we did not find a significant association between any of these, including p.L397F, with PDB. Osteoclastogenesis assays from the affected proband and his unaffected brother demonstrated an increase in osteoclast number and nucleation, consistent with the pagetic phenotype. In converse to other established Paget's associated genetic variations such as SQSTM1, TNFRSF11A and OPTN, expression of the mutant DC-STAMP protein attenuated the activation of transcription factors NFκB and AP-1 when exogenously expressed. We found that the p.L397F variant did not influence the subcellular localization of the protein. Based on these findings we conclude that genetic variation in DCSTAMP is not a significant predisposing factor in our specific cohort of PDB patients and the p.L397F variant is unlikely to be a contributing factor in PDB pathogenesis.