Genetic Determinants of Paget’s Disease of Bone

Makaram, Navnit S; Ralston, Stuart H.

doi:10.1007/s11914-021-00676-w

Cited by 15 publications

(12 citation statements)

References 105 publications

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“…For instance, patients with PDB have an elevated chance of developing osteosarcoma, and despite its rarity (0.3% of PDB individuals), vast majority of osteosarcomas (OS) diagnosed in adulthood occur in patients with PDB. Similarly, there have been observation of families in which PDB is accompanied by giant cell tumours (Makaram and Ralston, 2021). Early detection and treatment are crucial in preventing these complications and improving patient outcomes.…”

Section: Radiological Presentations In Pdbmentioning

confidence: 99%

“…Leontiasis ossea, a condition in which the facial bones become deformed, can also occur. The most severe consequences of PDB include osteosarcomas and other sarcomas (chondrosarcoma, fibrosarcoma), though their incidence is less than 1% ( Makaram and Ralston, 2021 ). In addition, PDB primarily affects the skeletal system, with certain regions being more prone to its impact than others ( Makaram et al, 2020 ), as seen in Figure 1 , the axial skeleton is the most commonly affected area ( Figure 2 ).…”

Section: Epidemiology Of Pdbmentioning

confidence: 99%

“…The genome wide scans have revealed several susceptibility loci for PDB and related syndromes ( Makaram and Ralston, 2021 ; Gennari et al, 2022 ). Most of these gene loci are linked to osteoclast differentiation or function.…”

Section: Epidemiology Of Pdbmentioning

confidence: 99%

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Paget’s disease: a review of the epidemiology, etiology, genetics, and treatment

et al. 2023

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Paget’s disease of bone (PDB) is the second most prevalent metabolic bone disorder worldwide, with a prevalence rate of 1.5%–8.3%. It is characterized by localized areas of accelerated, disorganized, and excessive bone production and turnover. Typically, PDB develops in the later stages of life, particularly in the late 50s, and affects men more frequently than women. PDB is a complex disease influenced by both genetic and environmental factors. PDB has a complex genetic basis involving multiple genes, with SQSTM1 being the gene most frequently associated with its development. Mutations affecting the UBA domain of SQSTM1 have been detected in both familial and sporadic PDB cases, and these mutations are often associated with severe clinical expression. Germline mutations in other genes such as TNFRSF11A, ZNF687 and PFN1, have also been associated with the development of the disease. Genetic association studies have also uncovered several PDB predisposing risk genes contributing to the disease pathology and severity. Epigenetic modifications of genes involved in bone remodelling and regulation, including RANKL, OPG, HDAC2, DNMT1, and SQSTM1, have been implicated in the development and progression of Paget’s disease of bone, providing insight into the molecular basis of the disease and potential targets for therapeutic intervention. Although PDB has a tendency to cluster within families, the variable severity of the disease across family members, coupled with decreasing incidence rates, indicates that environmental factors may also play a role in the pathophysiology of PDB. The precise nature of these environmental triggers and how they interact with genetic determinants remain poorly understood. Fortunately, majority of PDB patients can achieve long-term remission with an intravenous infusion of aminobisphosphonates, such as zoledronic acid. In this review, we discuss aspects like clinical characteristics, genetic foundation, and latest updates in PDB research.

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Section: Radiological Presentations In Pdbmentioning

confidence: 99%

Section: Epidemiology Of Pdbmentioning

confidence: 99%

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Paget’s disease: a review of the epidemiology, etiology, genetics, and treatment

et al. 2023

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“…These mutations usually affect the ubiquitin-associated domains of the proteins [ 81 ]. Other genes associated with risk of Paget’s disease include TNFRSF11A (encoding RANK) and TNFRSF11B (encoding OPG) [ 82 , 83 , 84 ]. Bone biopsy in Paget’s disease reveals a disorganized and poorly structured bone matrix.…”

Section: Sclerosing Disordersmentioning

confidence: 99%

Hereditary Metabolic Bone Diseases: A Review of Pathogenesis, Diagnosis and Management

Charoenngam

Nasr

Shirvani

et al. 2022

Genes

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Hereditary metabolic bone diseases are characterized by genetic abnormalities in skeletal homeostasis and encompass one of the most diverse groups among rare diseases. In this review, we examine 25 selected hereditary metabolic bone diseases and recognized genetic variations of 78 genes that represent each of the three groups, including sclerosing bone disorders, disorders of defective bone mineralization and disorder of bone matrix and cartilage formation. We also review pathophysiology, manifestation and treatment for each disease. Advances in molecular genetics and basic sciences has led to accurate genetic diagnosis and novel effective therapeutic strategies for some diseases. For other diseases, the genetic basis and pathophysiology remain unclear. Further researches are therefore crucial to innovate ways to overcome diagnostic challenges and develop effective treatment options for these orphan diseases.

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“…Two main hypotheses have been originally proposed, the genetic one and the one linked to the presence of environmental triggers (Roodman and Windle, 2005;Ralston et al, 2008;Gennari et al, 2019). Over the past two decades, important advances have been made in the field of cellular and molecular biology of PDB, and some genetic mutations have been identified as a possible cause of the disorder in up to 20%-30% of cases (Gennari et al, 2019;Makaram and Ralston, 2021). However, at least in a subset of cases, genetic susceptibility might not be a sufficient condition for the clinical development of PDB without…”

mentioning

confidence: 99%

Update on the pathogenesis and genetics of Paget’s disease of bone

Gennari

Rendina

Merlotti

et al. 2022

Front. Cell Dev. Biol.

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Studies over the past two decades have led to major advances in the pathogenesis of Paget’s disease of bone (PDB) and particularly on the role of genetic factors. Germline mutations of different genes have been identified, as a possible cause of this disorder, and most of the underlying pathways are implicated in the regulation of osteoclast differentiation and function, whereas other are involved in cell autophagy mechanisms. In particular, about 30 different germline mutations of the Sequestosome 1 gene (SQSTM1) have been described in a significant proportion of familial and sporadic PDB cases. The majority of SQSTM1 mutations affect the ubiquitin-binding domain of the protein and are associated to a more severe clinical expression of the disease. Also, germline mutations in the ZNF687 and PFN1 genes have been associated to severe, early onset, polyostotic PDB with increased susceptibly to neoplastic degeneration, particularly giant cell tumor. Mutations in the VCP (Valosin Containing Protein) gene cause the autosomal dominant syndrome “Inclusion Body Myopathy, PDB, Fronto-temporal Dementia,” characterized by pagetic manifestations, associated with myopathy, amyotrophic lateral sclerosis and fronto-temporal dementia. Moreover, germline mutations in the TNFRSF11A gene, which encodes for RANK, were associated with rare syndromes showing some histopathological, radiological, and clinical overlap with PDB and in two cases of early onset PDB-like disease. Likewise, genome wide association studies performed in unrelated PDB cases identified other potential predisposition genes and/or susceptibility loci. Thus, it is likely that polygenic factors are involved in the PDB pathogenesis in many individuals and that modifying genes may contribute in refining the clinical phenotype. Moreover, the contribution of somatic mutations of SQSTM1 gene and/or epigenetic mechanisms in the pathogenesis of skeletal pagetic abnormalities and eventually neoplastic degeneration, cannot be excluded. Indeed, clinical and experimental observations indicate that genetic susceptibility might not be a sufficient condition for the clinical development of PDB without the concomitant intervention of viral infection, in primis paramixoviruses, and/or other environmental factors (e.g., pesticides, heavy metals or tobacco exposure), at least in a subset of cases. This review summarizes the most important advances that have been made in the field of cellular and molecular biology PDB over the past decades.

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Genetic Determinants of Paget’s Disease of Bone

Cited by 15 publications

References 105 publications

Paget’s disease: a review of the epidemiology, etiology, genetics, and treatment

Paget’s disease: a review of the epidemiology, etiology, genetics, and treatment

Hereditary Metabolic Bone Diseases: A Review of Pathogenesis, Diagnosis and Management

Update on the pathogenesis and genetics of Paget’s disease of bone

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